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Departments of
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Molecular Immunology and
Immunobiology, Immunex Corp., Seattle, WA 98101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNF belongs to a family of structurally related molecules including
LT
,3 and the ligands
for CD27, CD30, CD40, OX40, 4–1BB, and Fas Ag (7, 8). When
administered exogenously either in vitro or in vivo, LT and TNF
elicit similar biologic responses and bind both known TNF receptors
(TNFR) with comparable affinities and kinetics (9). However, the extent
to which functional redundancy between endogenously produced TNF and
LT is physiologically relevant remains unclear. This issue is
further complicated by the identification of a related, membrane-bound
cytokine, LTß, that interacts with LT (10). The predominantly
expressed heteromeric complex of LT and LTß
(1ß2) does not bind either of the known
TNFR, but does bind to the LTßR gene product (11).
The biologic activities of TNF are mediated by two structurally related, but functionally distinct, receptors, p55 and p75, belonging to the TNFR gene family (6, 12, 13, 14). The two receptors are coexpressed on the surface of most cell types, and both are additionally proteolytically released as soluble molecules capable of binding TNF. A variety of approaches have been used to ascribe specific biologic functions to membrane-bound p55 and p75 receptors. Experiments using receptor-specific Abs (15, 16), receptor-specific ligands (17, 18), and mice genetically deficient in either p55 or p75 (19, 20, 21) indicate that p55 is the primary signaling receptor on most cell types through which the majority of inflammatory responses classically attributed to TNF occur. In contrast, TNF-induced thymocyte proliferation, TNF-mediated skin necrosis, and apoptosis of activated mature T lymphocytes are mediated by p75 (16, 22, 23). Two unique activities associated with membrane-bound p75 have recently been described. First, TNF associated with the cell surface is biologically active (24) and is superior to soluble TNF in triggering p75 (25). Additionally, surface-associated p75 is postulated to enhance p55-dependent responses by recruiting TNF to the cell surface and delivering the ligand to p55 in a ligand-passing model (26). However, it has recently been demonstrated that the enhancement of specific p55-dependent responses by p75 in fact does not involve ligand passing, but, rather, involves overlapping intracellular signaling events triggered by p55 and p75 (27).
A variety of inflammatory stimuli trigger the shedding of soluble p55 and p75 receptors from the cell surface into the circulation through proteolytic processing (28, 29). However, the extent to which endogenously produced soluble TNFR modulate TNF bioactivity remains unclear. Soluble TNFR could ostensibly function either as TNF antagonists, capable of neutralizing TNF bioactivity, or as TNF agonists, by prolonging the circulating half-life of TNF or by facilitating the interaction of TNF with membrane-bound receptors. An antagonistic role for soluble TNFR is supported by the observation that TNF has antiviral activity, and that a pox virus-encoded soluble TNFR, structurally most similar to p75, is an essential virulence gene (30). Additionally, exogenously administered recombinant soluble p55 or p75 Ig fusion proteins are effective TNF antagonists in several models of inflammation known to involve TNF (30, 31, 32, 33, 34).
In this report we have taken a genetic approach toward characterizing the physiologic functions of p55 and p75 in vivo as either signaling receptors or molecules capable of modulating TNF activity. Mice lacking p55, p75, and both p55 and p75 were created by gene targeting and analyzed. The results argue against an obvious role for these receptors, and hence TNF, in normal mouse development and homeostasis. However, selective deficits in host defense and inflammatory responses are observed in mice lacking p55 or both p55 and p75. Responses mediated by p55 are not dependent upon p75, arguing against an obligatory role for p75 in facilitating the interaction between TNF and p55. In contrast, p75-deficient mice exhibit an exacerbated p55-dependent pulmonary inflammatory response, suggesting a dominant role for endogenous p75 in attenuating leukocyte accumulation within the lung. TNF and IL-1 have been postulated to be critical mediators of lethal endotoxemia. However, mice genetically unable to respond to both TNF and IL-1 remain fully sensitive to the lethal effects of endotoxin. These data help clarify the physiologic functions of and interactions between the p55 and p75 receptors in mediating and modulating the biologic activities of TNF and indicate that endotoxin-induced sepsis syndrome in the mouse is independent of both TNF and IL-1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A genomic clone encoding murine p55 was isolated from a (CBA x C57BL/6)F1 genomic library (Clontech, Palo Alto, CA) and mapped by a combination of PCR and restriction analyzes. A targeting vector was constructed by replacing a 4-kb SpeI fragment encoding exons 2 to 5 (amino acids 30–184) with a PGK-neo cassette. A thymidine kinase cassette (MC-TK) was inserted into the 3' end of the vector. C57BL/6-derived ES cells (C. B. Ware, unpublished observations) were electroporated with the p55-targeting construct and selected as described previously (35). Approximately 1/20 G418 and ganciclovir-resistant clones carried a p55 allele disrupted by homologous recombination, as determined by PCR and genomic Southern blot analyses.
Targeting of the p75 TNFR gene by homologous recombination
A genomic clone encoding the ATG-containing exon of murine p75 was isolated from a 129 genomic library (Stratagene, La Jolla, CA) and mapped by PCR and restriction analyses. A targeting vector was constructed by replacing a 1-kb KasI-BamHI fragment encoding amino acids 3 to 26 with a PGK-neo cassette. A MC-TK cassette was inserted into the 5' end of the vector. 129-derived AB1 ES (36) cells were electroporated with the p75 targeting construct and selected as described above. Approximately 1/400 G418 and ganciclovir-resistant clones carried a p75 allele disrupted by homologous recombination as determined by PCR and genomic Southern blot analyses.
Generation of p55 and p75 TNFR-deficient mice
p55- and p75-targeted ES cell clones were injected into day 3.5 BALB/c and C57BL/6 blastocysts, respectively, and transferred to day 2.5 pseudopregnant Swiss-Webster recipients. Resulting male chimeras were bred to C57BL/6 females, and offspring were analyzed for germ-line transmission of the mutant alleles by PCR and genomic Southern blot analyses. Mice heterozygous for either p55 or p75 mutations (p55+/- and p75+/-, respectively) were intercrossed to yield mice homozygous for the respective mutations (p55-/- and p75-/-). Mice heterozygous for both TNFR mutations (p55+/-p75+/-) were generated by crosses between p55-/- and p75-/- mice and subsequently intercrossed to derive p55 and p75 TNFR doubly deficient mice (p55-/-p75-/-). Genotyping was performed using a combination of PCR and genomic Southern analyses.
Mouse strains
The p55-/- mice used in this study were C57BL/6 inbred. The p75-/- and p55-/-p75-/-mice were maintained as random C57BL/6 x 129 hybrids, unless indicated otherwise. In some experiments, p75-/- and p55-/-p75-/- mice on a C57BL/6 background (B6N5 p75-/- and B6N4 p55-/-p75-/-, respectively) were generated by successive backcrossing to C57BL/6 for four (B6N4) or five (B6N5) generations and analyzed. C57BL/6 (Charles River, Wilmington, MA), 129/J, and (129/J x C57BL/6)F1 (The Jackson Laboratory, Bar Harbor, ME) mice were used as controls as indicated in the text. Mice heterozygous for either TNFR mutation and the type 1 IL-1R mutation (p55+/-IL-1R+/-, p75+/-IL-1R+/-) were generated by crosses between, respectively, p55-/- and p75-/- mice and IL-1R-/- mice (37) and subsequently intercrossed to derive p55-/-IL-1R-/- and p75-/-IL-1R-/- mice on random C57BL/6 x 129 hybrid backgrounds. Genotyping was performed using a combination of PCR and genomic Southern analyses. For bone marrow reconstitution experiments, 8-wk-old C57BL/6 females were lethally irradiated (950 rad) using a 137Cs source (J. L. Shepard Co., Glendale, CA) at 89 rad/min and injected i.v. with 1 x 106 bone marrow cells pooled from femurs of three C57BL/6 or three p55-/- mice. Reconstituted mice were analyzed 8 wk following bone marrow transfer.
Binding analyses
Murine TNF- (PeproTech, Rocky Hills, NJ) was biotinylated
using biotin-X-NHS (Calbiochem, San Diego, CA) according to
manufacturer’s specifications. Approximately 2 x
105 cells in a final volume of 25 µl were incubated
with biotinylated TNF and streptavidin-conjugated phycoerythrin (Becton
Dickinson, San Jose, CA) and analyzed by flow cytometry (38).
Thymocytes from adult mice were cultured in RPMI 1640 supplemented with
10% FCS, 0.5 mM ß-ME, glutamine, and 10 µg/ml Con A for 18 h
before use in binding assays. Peritoneal exudate cells were lavaged
from the peritoneal cavity in 10 ml of ice-cold RPMI 1640 supplemented
with 10% FCS 3 days following i.p. injection of 1 ml of 5%
thioglycolate broth (Sigma). Bronchoalveolar lavage (BAL) cells were
prepared, as described below, 4 h after intranasal LPS
administration.
Flow cytometric and histologic analyses of lymphoid organs
Thymic, splenic, and peripheral lymph node cellularities and subset distributions were determined by flow cytometric analyses using a variety of cell surface markers as described previously (39). Spleens were fixed in formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.
Acute phase responses
Mice (8–12 wk of age) were injected i.p. with 2.4 µg/g of body weight LPS (Escherichia coli strain 0127-B8, Difco, Detroit, MI). At the indicated times, mice were killed by cervical dislocation, and liver biopsies were collected. Total liver RNA was isolated and subjected to Northern blot analyses using PCR-generated cDNA probes encoding various acute phase reactants.
Listeria monocytogenes infection
Mice were lightly anesthetized with Metafane (Pitman-Moore, Mundelein, IL), injected i.v. via the orbital plexus with live Listeria monocytogenes (40249, American Type Culture Collection, Rockville, MD) in PBS, and monitored twice daily for survival. Splenic bacterial loads were determined at various times postinfection by harvesting spleens from surviving animals, homogenizing in dH2O/0.01% BSA, and plating out serial dilutions onto brain heart infusion agar plates. Colonies were enumerated after incubation for 24 h at 37°C.
Endotoxic shock
Susceptibility to LPS was assessed by injecting mice (8–16 wk of age) i.p. with 35 to 50 µg/g of body weight LPS (E. coli strain 0127-B8, Difco) and monitoring twice daily for at least 10 days. Susceptibility to LPS in conjunction with D-galactosamine (D-gal) was assessed by i.v. coinjection into the tail vein of 0.5 to 2.5 ng of LPS (E. coli strain 0127-B8, Difco)/g of body weight and 20 mg D-gal (Sigma) and monitoring twice daily for at least 5 days.
Intranasal instillation and BAL
Pulmonary inflammation was induced by intranasal administration of either LPS (E. coli strain 0127-B8, Difco) or Micropolyspora faeni (M. faeni, American Type Culture Collection 15347). LPS stock solutions were prepared at 1.8 mg/ml in saline. Lyophilized M. faeni Ag was prepared as described previously (40) from sonicated M. faeni cultures and reconstituted in saline at a concentration of 1.36 mg/ml. Endotoxin levels were determined to be 1.6 pg/mg M. faeni Ag using a Limulus amoebocyte lysate assay (Sigma). Age-matched animals were lightly anesthetized with Metafane before intranasal instillation of either LPS or M. faeni Ag stock solutions. Fifty-five microliters of LPS stock solution (100 µg) was administered, and BAL was performed 22 h later. Fifty-five microliters of reconstituted M. faeni solution (75 µg) was administered as described above daily for 3 days. BAL was performed either 2 or 24 h following the third instillation. BAL following either LPS or M. faeni instillations was performed by repeated lavage of airways with 1 ml of 0.6 µM EDTA in PBS for a total of 5 ml. BAL cell counts were determined using a Coulter counter (Hialeah, FL). BAL compositions were determined on cytospins stained using Diffquik (Baxter, McGaw Park, IL).
Cytokine determination
Levels of total TNF- were determined by ELISA according to
the manufacturer’s specifications (Genzyme, Cambridge, MA). Levels of
biologically active TNF- were determined using the L929 cytotoxicity
assay in conjunction with crystal violet (0.5% in 25% methanol) as
described previously (33).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice lacking functional p55 and p75 TNFR genes were
generated by gene targeting in ES cells using the constructs outlined
in Figure 1
, A and
B. Southern blot analyses using diagnostic restriction
digests in conjunction with probes lying outside the regions of
homology contained within the targeting vectors confirm that the TNFR
genes were disrupted by homologous recombination (Fig. 1, C
and D). The p55 mutation was generated in a C57BL/6
ES cell. Germ-line transmission of the altered p55 allele from chimeras
created with BALB/c blastocysts demonstrated that C57BL/6 ES cells were
a practical alternative to the traditionally used, 129-derived ES cell
lines. p55-deficient mice (p55-/-) and p75-deficient mice
(p75-/-) were generated at the expected Mendelian
frequencies from crosses between p55+/- and
p75+/- parents, respectively (data not shown). p55 and p75
doubly deficient mice (p55-/-p75-/-) as
well as p55-/-IL-1R-/- and
p75-/-IL-1R-/- mice were generated at the
expected frequencies from crosses of, respectively,
p55+/-p75+/-,
p55+/-IL-1R+/-, and
p75+/-IL-1R+/- parents (data not shown). None
of the three TNFR-deficient or TNFR- and IL-1R-deficient strains
displayed any gross phenotypic or reproductive anomalies.
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A, Con A-stimulated
thymocytes from p55-/-p75-/- mice failed to
bind murine TNF. It is also apparent that p75 was the predominant TNF
binding moiety on these cells, as binding to p75-/- cells
was minimal, and binding to p55-/- cells was comparable
to that observed to wild-type cells. As observed with Con A-stimulated
thymocytes, there was no detectable binding of murine TNF to
thioglycolate-elicited peritoneal exudate cells from
p55-/-p75-/- mice (Fig. 2B). The composition of cells from exudates of
p55-/-p75-/- mice was
indistinguishable from that of cells from exudates from control mice
(data not shown). Additionally, exudate cells from p55 or p75 singly
deficient mice displayed TNF binding profiles distinct from those of
controls, indicating that both receptors were normally expressed on
this population of cells and that TNF binding to either receptor was
not strictly dependent upon the presence of the second receptor.
Lastly, no binding of biotinylated murine TNF was observed to
p55-/-p75-/- cells, predominantly
neutrophils, lavaged from the lungs of mice 4 h after intranasal
administration of LPS (data not shown). Collectively, these data
indicated that p55 and p75 together comprised the sole TNF binding
moieties on the surface of the cell types analyzed.
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Analyses of thymic cellularity and subpopulations
from young adult p55-/-, p75-/-, and
p55-/-p75-/- mice revealed that although
TNF is constitutively expressed in the thymus and is
capable of stimulating thymocyte proliferation, thymopoiesis
was not critically dependent upon TNFR (Fig. 3A). Additionally,
similar analyses of peripheral lymphoid organs of
p55-/-p75-/- mice using surface markers
specific for B and T cell lineages indicated that lymphoid development
was not dependent upon TNF (Fig. 3, B and
C). Moreover, the total lymphoid cellularity of
thymi, spleens, and mesenteric lymph nodes from
p55-/-p75-/- mice was comparable to that
observed in control mice (data not shown). Lastly, gross histologic
analyses of hematoxylin- and eosin-stained sections of spleens and
mesenteric and inguinal lymph nodes derived from
p55-/-, p75-/-, and
p55-/-p75-/- mice did not reveal
any obvious anomalies (data not shown).
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Injection of mice with the intracellular pathogen L.
monocytogenes leads to an acute infection. Early resistance to
infection requires activation of macrophage microbicidal activity and
is critically dependent upon TNF and IFN-
(3). Later developing
sterilizing immunity is dependent upon functional T cells (41). As
shown in Figure 4A and as
previously reported (19, 20), mice genetically deficient in p55
succumbed to an otherwise sublethal infection of L.
monocytogenes. In contrast, survival of p75-/- and
B6N5 p75-/- mice following L. monocytogenes
infection was comparable to that observed in controls (Fig. 4, A and B). Splenic bacterial loads in
p75-/- mice 5 days postinfection were similar to those
displayed by control mice, and by day 21, viable bacteria were no
longer recovered from either p75-/- or control spleens
(data not shown).
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LPS is a potent inducer of TNF expression, and serum TNF levels
rapidly rise following in vivo administration of LPS (1). The
concentration of total serum TNF 2 h post-LPS challenge, as
determined by ELISA, was elevated approximately 5-fold in mice lacking
either p55 or p75 relative to that in wild-type mice and 15- to 20-fold
in mice lacking both p55 and p75 (Fig. 5
and data not shown). Whereas the p55 and p75 mutations clearly
influence the magnitude of the TNF response, the kinetics of TNF
appearance and disappearance following LPS exposure are grossly
unaffected in mice lacking either or both p55 or p75 (Fig. 5). The
levels of biologically active TNF, as assessed by cytotoxic activity in
the L929 bioassay, in wild-type mice and in mice lacking either or both
p55 and p75 mirrored the levels determined by ELISA (data not
shown).
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LPS administration induces the synthesis of a series of acute
phase reactants by the liver (42). This response has been shown to
involve TNF, IL-1, and members of the IL-6 cytokine family. As shown in
Figure 6, the magnitude and kinetics of
induction of several acute phase reactants in the livers of
p55-/-p75-/- mice were comparable to
those observed in controls. These data argue against an obligate
participation of TNF in the induction of the hepatic acute phase
response by LPS.
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The lethal effects of LPS have been attributed to the massive
induction of proinflammatory cytokine synthesis and release. TNF and
IL-1 are thought to be critical mediators of endotoxin-induced septic
shock. Mice treated with the hepatotoxin D-gal are
rendered extremely sensitive to LPS (43, 44). As shown in Table I, p55-/- and
p55-/-p75-/- mice, but not
p75-/- mice, were protected from a lethal dose of LPS
(2.5 ng/g of body weight) plus D-gal. Although the mice
were monitored for at least 5 days, all susceptible mice succumbed to
LPS plus D-gal treatment within 2 days, whereas resistant
mice displayed no obvious symptoms at any time following treatment.
Similar results using independently derived p55- and p75-deficient mice
have previously been reported (19, 20, 21). Lethality associated with LPS
and D-gal is TNF dependent and requires p55. To examine the
extent to which endogenous p75 modulates this response, control and
TNFR-deficient mice were challenged with a sublethal dose of LPS (0.5
ng/g of body weight) plus D-gal. A slightly increased
sensitivity to a sublethal dose of LPS plus D-gal was
observed in p75-deficient mice (Table I).
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and
data not shown). These data indicated that lethality in this model was
not strictly dependent upon TNF. To investigate the contribution of
IL-1 in the induction of lethal endotoxemia in mice lacking TNFR, mice
lacking either p55 or p75 and the type 1 IL-1R were generated and
analyzed. p55-/-IL-1R-/- and
p75-/-IL-1R-/- mice remained susceptible to
LPS and succumbed to lethal endotoxemia with kinetics comparable to
those observed in controls (Fig. 7,
A and B).
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Leukocyte emigration into the lung is induced by systemic
administration or direct inhalation of various inflammatory agents and
is associated with pulmonary pathology. Intranasal instillation of
heat-inactivated actinomycete M. faeni Ags into mice induces
hypersensitivity pneumonitis. Disease induction is associated with
elevated TNF production within the lung and can be prevented using
neutralizing anti-TNF Abs (40, 45). The initial pulmonary influx of
neutrophils in response to M. faeni was examined in p55- and
p75-deficient mice. M. faeni-induced neutrophil accumulation
within the lung was dramatically decreased in p55-/- and
p55-/-p75-/- mice relative to
that observed in control mice, whereas the levels of monocytes and
lymphocytes within the lung were comparable in all strains (Fig. 8A). In contrast, an
exacerbated neutrophil influx was observed in the lungs of
p75-/- mice, whereas the levels of monocytes and
lymphocytes within the lung were not affected by the mutation.
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B). The genotypes of
the emigrating cells were confirmed by genomic PCR analyses of BAL
cells (Fig. 8C) and indicated that p55-deficient
neutrophils could properly traffic into a wild-type lung. To examine further the role of TNF in pulmonary inflammation, neutrophil emigration into the lungs of TNFR-deficient mice was examined following intranasal administration of LPS. In this model, neutrophil accumulation within the lung in mice lacking p55, p75, or both p55 and p75 was comparable to that observed in wild-type mice (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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p55 and p75 are expressed by most cell types. The observation that mice
deficient in both p55 and p75 are overtly normal indicates that neither
p55 nor p75, and hence TNF, are grossly required for normal mouse
development and homeostasis under basal conditions. Recent analyses of
mice specifically lacking TNF support these observations (46). These
observations are in marked contrast to the phenotype observed in mice
lacking LT, a cytokine that is structurally and functionally related
to TNF. LT-deficient mice lack lymph nodes (47). It is apparent from
these studies as well as those previously described (19, 20, 21) that this
phenotype is not shared by mice singly deficient in either p55 or p75.
Moreover, we have extended these observations by demonstrating that
mice lacking both p55 and p75 are also phenotypically distinct from
LT-deficient mice with regard to lymph node development. These
observations clearly indicate that despite the functional redundancy
between TNF and LT defined in vitro, endogenous LT can function
independently of both p55 and p75 in vivo. LT associates on the cell
surface with LTß (10). As the resulting heteromeric complex does not
bind either p55 or p75, but, rather, interacts with the recently
identified LTßR (11), it is likely that defective lymph node
development in LT-deficient mice is due to an inability to trigger
LTßR. These observations do not exclude a role for p55 or p75 in
mediating other activities associated with LT in vivo. Shared
defects between LT- and TNFR-deficient mice may define such
activities. For example, we have recently demonstrated that germinal
center formation is defective in mice lacking either LT or p55 (48).
Additionally, it has recently been observed that the development of
Peyer’s patches is defective in p55-deficient mice (49) (J. J.
Peschon, unpublished observation). The extent to which either of these
shared defects reflects activities of LT that require p55 remains to
be established. Mice lacking p55 or TNF also display defects in primary
B cell follicles and follicular dendritic cell networks, indicating yet
additional roles for TNF and TNFR in lymphoid structure and function
(46, 50). Future investigations using mice lacking TNF, lymphotoxin,
and their receptors are directed at determining the extent to which
signals transduced by TNFRs and LTßR might themselves be redundant.
Phenotypic differences between these strains might in part represent
exclusive or restricted profiles of expression of these molecules
rather than functionally distinct signaling mechanisms.
The data presented in this report do not reveal a specific role for p75 in delivering a TNF-dependent signal in vivo. However, it is clear from a number of studies that p75 is a signaling receptor for TNF. For example, it has recently been demonstrated that activation-induced cell death of T cells is mediated by both p75 and Fas (23). Additionally, p75 is involved in the development of necrotizing skin lesions induced by s.c. administration of TNF (16, 21). The role of endogenous p75 in modulating the activity of TNF in vivo is less clear. p75 has been proposed to increase the sensitivity of cells to TNF through ligand passing to p55 (26), although an alternative explanation for the ability of p75 to enhance p55-mediated responses is that the two receptors can impinge upon overlapping or identical signal transduction pathways (27). Additionally, both soluble p55 and p75 can stabilize TNF and thus potentially function as TNF agonists (51). However, it is also apparent that soluble TNFRs can function as effective TNF antagonists. For example, administration of a soluble p75 Ig fusion protein is effective in reducing mortality in an animal model of endotoxemia (33) and decreases the incidence and the severity of disease in a model of collagen-induced arthritis (34). Additionally, pox virus genomes harbor open reading frames encoding soluble TNFRs structurally most similar to p75, which are essential for virulence (30). While inflammatory stimuli induce the proteolytic shedding of both p55 and p75, levels of soluble p75 greatly exceed those of soluble p55 and thus suggest a dominant role for endogenously produced soluble p75 in down-regulating TNF-driven responses (28, 29, 51). In this report we have used mice genetically deficient in either p55 or p75 to define, firstly, those responses that are dependent upon p55 and, secondly, the extent to which p75 can modulate these responses.
Mice lacking either p55 or p75 accumulate increased levels of TNF
relative to controls following LPS administration. These observations
indicate that both p55 and p75 play a role in regulating steady state
TNF levels. It will be of interest to determine whether this regulation
is dependent upon cell surface-associated or soluble TNFR. In this
regard, it is of interest to note that the serum levels of LPS-induced
soluble p55 TNFR are unaffected by the p75 mutation, and the serum
levels of LPS-induced soluble p75 TNFR are unaffected by the p55
mutation (J. J. Peschon, unpublished observation). The elevated
TNF levels in p55-deficient mice are predicted to be inconsequential
with respect to most inflammatory responses involving TNF, as these
appear to be predominantly mediated by p55 itself. However, the
elevated levels of TNF observed in mice lacking p75 might lead to
increased TNF sensitivity in responses that are mediated by p55. For
example, we have demonstrated that neutrophil influx into the lung
induced by intranasal administration of M. faeni Ags is TNF
dependent and requires p55 expression within a radiation-resistant
component of the lung microenvironment. Neutrophil influx in this model
can be attenuated by coadministration of a soluble p75 Ig fusion
protein.4 In this model, mice
lacking p75 display an exacerbated response, suggesting a role for
endogenous p75 in down-modulating pulmonary inflammatory responses. The
phenotype of p55-/-p75-/- mice resembles
that observed in p55-/- mice, indicating that the
exacerbated response remains dependent upon a functional interaction
between TNF and p55. In contrast, pulmonary neutrophil influx in
response to LPS is normal in mice lacking either or both p55 and p75,
suggesting that this response neither requires nor is modulated by TNF.
The cytokines driving this latter response are not known, although
molecules such as macrophage inflammatory protein-1 are logical
candidates, as macrophage inflammatory protein-1 is expressed in the
lung following inflammatory challenge and is a potent inducer of
neutrophil infiltration into the lung (52, 53). Thus, there exist both
TNF-dependent and TNF-independent pathways of leukocyte emigration into
the lung. The clinical efficacy of TNF antagonists will certainly be
influenced by which pathways are activated during disease states
leading to pulmonary inflammation.
As described here and previously (19, 20, 21), lethal shock induced by LPS
and D-gal coadministration requires p55 and not p75.
Additionally, we demonstrate that p75-deficient mice remain susceptible
to shock induced by a sublethal dose of LPS and D-gal, in
which TNF is presumably limiting. This observation argues against
agonistic or ligand-passing roles for p75 in this TNF-dependent
response. In fact, the slightly elevated lethality observed in
p75-deficient mice might, rather, reflect a role for p75 in attenuating
the toxic effects of TNF in this model. In contrast to septic shock
elicited specifically by D-gal and either endotoxin or
enterotoxin treatment, in which lethality is clearly dependent upon
TNF, it remains unclear which cytokines are critical for mediating the
lethal effects of high doses of LPS alone. p75-deficient mice were
reported to be less sensitive to the lethal effects of intermediate
doses of LPS, and this reduced sensitivity was attributed to an
enhancing or agonistic role of p75 in mediating the lethal effects of
TNF through the p55 receptor (21). These data imply that TNF is
involved in host sensitivity to LPS. However, as demonstrated here and
reported previously (19, 20), mice lacking p55 remain sensitive to the
lethal effects of intermediate or high dose LPS administration,
indicating that lethality in this model is clearly p55 independent.
Moreover, we find that p75-deficient mice are not less sensitive to
high or intermediate doses of LPS. Although we cannot exclude the
possibility that subtle variations in experimental regimens or genetic
backgrounds contribute to this discrepancy, our observation that mice
lacking both p55 and p75 remain as sensitive as controls to
intermediate and high doses of LPS strongly indicates that lethality in
this model is TNF independent. The cytokines mediating lethal sepsis in
wild-type and TNFR-deficient mice remain undefined. We considered the
involvement of IL-1, as IL-1 antagonists are protective in some animal
models of endotoxemia and mice lacking the IL-1ß-converting enzyme
(ICE), which fail to process IL-1ß and additionally show reduced TNF
production, are resistant to high doses of LPS (54, 55). However, we
have recently generated mice lacking the type 1 IL-1R (37) and used
these to generate mice lacking both p55 and type 1 IL-1R and mice
lacking both p75 and type 1 IL-1R. Surprisingly, these doubly deficient
strains remain sensitive to the lethal effects of high doses of LPS. It
has recently been reported that ICE is also required for the
proteolytic processing of IFN--inducing factor (56). In light of
this observation and the data reported here, LPS resistance in mice
lacking ICE is probably independent of both IL-1 and TNF and instead is
mediated by defects in the production of IFN- or other
proinflammatory cytokines. These observations underscore the potential
for cytokine redundancy in the inflammatory cascade leading to septic
shock.
The role of TNF in innate resistance to bacterial infection is well established (57, 58), and as shown here and previously reported (19, 20), mice lacking p55 are rendered highly susceptible to infection by the intracellular pathogen L. monocytogenes. A percentage of mice deficient in p75, maintained on a mixed C57BL/6 x 129 genetic background, were previously reported to have decreased resistance to L. monocytogenes infection due to a proposed requirement for p75 in facilitating an efficient interaction between TNF and p55 (21). However, 129 mice are naturally sensitive, and C57BL/6 mice are naturally resistant to L. monocytogenes, with resistance being genetically determined by the dominant Lsr-1r allele (59). Thus, a fraction of random C57BL/6 x 129 hybrid mice are expected to display increased sensitivity to L. monocytogenes independent of any targeted mutation. We have examined L. monocytogenes susceptibility of p75-deficient mice maintained on both C57BL/6 and hybrid C57BL/6 x 129 genetic backgrounds and have found that p75-deficient mice do not display impaired resistance to L. monocytogenes. Moreover, administration of neutralizing Abs to either TNF or p55 renders mice extremely susceptible to Listeria, whereas administration of Abs against p75 does not impair L. monocytogenes resistance (16). Thus, the activity of TNF in innate resistance to Listeria requires p55 and is independent of p75.
In this report we have examined the physiologic function of p55 and p75 in vivo as either signaling receptors or as molecules capable of modulating TNF activity. We demonstrate that a p55-dependent response, namely neutrophil trafficking into the lung, is exacerbated in mice lacking p75. Our observation that the levels of TNF in the circulation of challenged p75-deficient mice are dramatically elevated relative to those observed in challenged wild-type mice provides a potential mechanism for this exacerbated response. The extent to which endogenous p75 regulates other p55-dependent responses in either acute or chronic inflammatory settings warrants further investigation.
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2 Present address: Department of Comparative Medicine, University of Washington, Seattle, WA 98195.
3 Abbreviations used in this paper: LT, lymphotoxin ; TNFR, tumor necrosis factor receptor; LTß, lymphotoxin ß, LTßR, lymphotoxin ß receptor; PGK-neo, phosphoglycerol kinase-neomycin resistance gene; TK, thymidine kinase; ES cell, embryonic stem cell; BAL, bronchoalveolar lavage; D-gal, D-galactosamine; ICE, interleukin-1ß-converting enzyme.
4 K. M. Mohler, D. Torrance, M. Glaccum, C. Otten, and R. A. Black. Neutrophil influx into the lungs of mice exposed to Micropolyspora faeni anitgen is dependent upon TNF but not IL-1. Submitted for publication.
Received for publication June 27, 1997. Accepted for publication October 1, 1997.
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T. W. Wright, G. S. Pryhuber, P. R. Chess, Z. Wang, R. H. Notter, and F. Gigliotti TNF Receptor Signaling Contributes to Chemokine Secretion, Inflammation, and Respiratory Deficits during Pneumocystis Pneumonia J. Immunol., February 15, 2004; 172(4): 2511 - 2521. [Abstract] [Full Text] [PDF]
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 G. Krueger and K. Callis Potential of Tumor Necrosis Factor Inhibitors in Psoriasis and Psoriatic Arthritis Arch Dermatol, February 1, 2004; 140(2): 218 - 225. [Abstract] [Full Text] [PDF]
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T. E. Riehl, R. D. Newberry, R. G. Lorenz, and W. F. Stenson TNFR1 mediates the radioprotective effects of lipopolysaccharide in the mouse intestine Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G166 - G173. [Abstract] [Full Text] [PDF]
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O. Tliba, S. Tliba, C. Da Huang, R. K. Hoffman, P. DeLong, R. A. Panettieri Jr., and Y. Amrani Tumor Necrosis Factor {alpha} Modulates Airway Smooth Muscle Function via the Autocrine Action of Interferon {beta} J. Biol. Chem., December 12, 2003; 278(50): 50615 - 50623. [Abstract] [Full Text] [PDF]
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Y. CHEN, Q. KE, Y. YANG, J. S. RANA, J. TANG, J. P. MORGAN, and Y.-F. XIAO Cardiomyocytes overexpressing TNF-{alpha} attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase FASEB J, December 1, 2003; 17(15): 2231 - 2239. [Abstract] [Full Text] [PDF]
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P. Lundberg, P. Welander, H. Openshaw, C. Nalbandian, C. Edwards, L. Moldawer, and E. Cantin A Locus on Mouse Chromosome 6 That Determines Resistance to Herpes Simplex Virus Also Influences Reactivation, While an Unlinked Locus Augments Resistance of Female Mice J. Virol., November 1, 2003; 77(21): 11661 - 11673. [Abstract] [Full Text] [PDF]
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H. Chiu, C. R. Gardner, D. M. Dambach, J. A. Brittingham, S. K. Durham, J. D. Laskin, and D. L. Laskin Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G959 - G966. [Abstract] [Full Text] [PDF]
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T. A. Moore, M. L. Perry, A. G. Getsoian, C. L. Monteleon, A. L. Cogen, and T. J. Standiford Increased Mortality and Dysregulated Cytokine Production in Tumor Necrosis Factor Receptor 1-Deficient Mice following Systemic Klebsiella pneumoniae Infection Infect. Immun., September 1, 2003; 71(9): 4891 - 4900. [Abstract] [Full Text] [PDF]
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H. Chen, O. Tliba, C. R. Van Besien, R. A. Panettieri Jr., and Y. Amrani Selected Contribution: TNF-{alpha} modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl J Appl Physiol, August 1, 2003; 95(2): 864 - 872. [Abstract] [Full Text] [PDF]
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R. G. Lorenz, D. D. Chaplin, K. G. McDonald, J. S. McDonough, and R. D. Newberry Isolated Lymphoid Follicle Formation Is Inducible and Dependent Upon Lymphotoxin-Sufficient B Lymphocytes, Lymphotoxin {beta} Receptor, and TNF Receptor I Function J. Immunol., June 1, 2003; 170(11): 5475 - 5482. [Abstract] [Full Text] [PDF]
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J. Corredor, F. Yan, C. C. Shen, W. Tong, S. K. John, G. Wilson, R. Whitehead, and D. B. Polk Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms Am J Physiol Cell Physiol, April 1, 2003; 284(4): C953 - C961. [Abstract] [Full Text] [PDF]
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 A. S. De Vriese Prevention and Treatment of Acute Renal Failure in Sepsis J. Am. Soc. Nephrol., March 1, 2003; 14(3): 792 - 805. [Full Text] [PDF]
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 G. S. Pryhuber, H. L. Huyck, R. Baggs, G. Oberdorster, and J. N. Finkelstein Induction of Chemokines by Low-Dose Intratracheal Silica Is Reduced in TNFR I (p55) Null Mice Toxicol. Sci., March 1, 2003; 72(1): 150 - 157. [Abstract] [Full Text] [PDF]
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M. Pandey, G. Tuncman, G. S. Hotamisligil, and F. Samad Divergent Roles for p55 and p75 TNF-{alpha} Receptors in the Induction of Plasminogen Activator Inhibitor-1 Am. J. Pathol., March 1, 2003; 162(3): 933 - 941. [Abstract] [Full Text] [PDF]
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J. Schumann, K. Muhlen, A. K. Kiemer, A. M. Vollmar, and G. Tiegs Parenchymal, But Not Leukocyte, TNF Receptor 2 Mediates T Cell-Dependent Hepatitis in Mice J. Immunol., February 15, 2003; 170(4): 2129 - 2137. [Abstract] [Full Text] [PDF]
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 K. Akassoglou, E. Douni, J. Bauer, H. Lassmann, G. Kollias, and L. Probert Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice PNAS, January 21, 2003; 100(2): 709 - 714. [Abstract] [Full Text] [PDF]
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J. H. Wang, M. Doyle, B. J. Manning, S. Blankson, Q. D. Wu, C. Power, R. Cahill, and H. P. Redmond Cutting Edge: Bacterial Lipoprotein Induces Endotoxin-Independent Tolerance to Septic Shock J. Immunol., January 1, 2003; 170(1): 14 - 18. [Abstract] [Full Text] [PDF]
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L. M. Sedger, S. Hou, S. R. Osvath, M. B. Glaccum, J. J. Peschon, N. van Rooijen, and L. Hyland Bone Marrow B Cell Apoptosis During In Vivo Influenza Virus Infection Requires TNF-{alpha} and Lymphotoxin-{alpha} J. Immunol., December 1, 2002; 169(11): 6193 - 6201. [Abstract] [Full Text] [PDF]
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M. A. Koay, J. W. Christman, L. J. Wudel, T. Allos, D.-S. Cheng, W. C. Chapman, and T. S. Blackwell Modulation of endotoxin-induced NF-kappa B activation in lung and liver through TNF type 1 and IL-1 receptors Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1247 - L1254. [Abstract] [Full Text] [PDF]
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A. Kanehiro, M. Lahn, M. J. Makela, A. Dakhama, A. Joetham, Y.-H. Rha, W. Born, and E. W. Gelfand Requirement for the p75 TNF-{alpha} Receptor 2 in the Regulation of Airway Hyperresponsiveness by {gamma}{delta} T Cells J. Immunol., October 15, 2002; 169(8): 4190 - 4197. [Abstract] [Full Text] [PDF]
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A. Churg, J. Dai, H. Tai, C. Xie, and J. L. Wright Tumor Necrosis Factor-{alpha} Is Central to Acute Cigarette Smoke-induced Inflammation and Connective Tissue Breakdown Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 849 - 854. [Abstract] [Full Text]
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A. A. Ragab, J. L. Nalepka, Y. Bi, and E. M. Greenfield Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells Am J Physiol Cell Physiol, September 1, 2002; 283(3): C679 - C687. [Abstract] [Full Text] [PDF]
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T. Kagari, H. Doi, and T. Shimozato The Importance of IL-1{beta} and TNF-{alpha}, and the Noninvolvement of IL-6, in the Development of Monoclonal Antibody-Induced Arthritis J. Immunol., August 1, 2002; 169(3): 1459 - 1466. [Abstract] [Full Text] [PDF]
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L. Li, A. Khansari, L. Shapira, D. T. Graves, and S. Amar Contribution of Interleukin-11 and Prostaglandin(s) in Lipopolysaccharide-Induced Bone Resorption In Vivo Infect. Immun., July 1, 2002; 70(7): 3915 - 3922. [Abstract] [Full Text] [PDF]
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N. Cusson, S. Oikemus, E. D. Kilpatrick, L. Cunningham, and M. Kelliher The Death Domain Kinase RIP Protects Thymocytes from Tumor Necrosis Factor Receptor Type 2-induced Cell Death J. Exp. Med., July 1, 2002; 196(1): 15 - 26. [Abstract] [Full Text] [PDF]
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H. Ji, A. Pettit, K. Ohmura, A. Ortiz-Lopez, V. Duchatelle, C. Degott, E. Gravallese, D. Mathis, and C. Benoist Critical Roles for Interleukin 1 and Tumor Necrosis Factor {alpha} in Antibody-induced Arthritis J. Exp. Med., July 1, 2002; 196(1): 77 - 85. [Abstract] [Full Text] [PDF]
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P. N. Cunningham, H. M. Dyanov, P. Park, J. Wang, K. A. Newell, and R. J. Quigg Acute Renal Failure in Endotoxemia Is Caused by TNF Acting Directly on TNF Receptor-1 in Kidney J. Immunol., June 1, 2002; 168(11): 5817 - 5823. [Abstract] [Full Text] [PDF]
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R. D. Newberry, J. S. McDonough, K. G. McDonald, and R. G. Lorenz Postgestational Lymphotoxin/Lymphotoxin {beta} Receptor Interactions Are Essential for the Presence of Intestinal B Lymphocytes J. Immunol., May 15, 2002; 168(10): 4988 - 4997. [Abstract] [Full Text] [PDF]
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A. H. van Houwelingen, M. Kool, S. C. A. de Jager, F. A. M. Redegeld, D. van Heuven-Nolsen, A. D. Kraneveld, and F. P. Nijkamp Mast Cell-Derived TNF-{alpha} Primes Sensory Nerve Endings in a Pulmonary Hypersensitivity Reaction J. Immunol., May 15, 2002; 168(10): 5297 - 5302. [Abstract] [Full Text] [PDF]
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J. R. Maxwell, C. Ruby, N. I. Kerkvliet, and A. T. Vella Contrasting the Roles of Costimulation and the Natural Adjuvant Lipopolysaccharide During the Induction of T Cell Immunity J. Immunol., May 1, 2002; 168(9): 4372 - 4381. [Abstract] [Full Text] [PDF]
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S. Smith, D. Liggitt, E. Jeromsky, X. Tan, S. J. Skerrett, and C. B. Wilson Local Role for Tumor Necrosis Factor Alpha in the Pulmonary Inflammatory Response to Mycobacterium tuberculosis Infection Infect. Immun., April 1, 2002; 70(4): 2082 - 2089. [Abstract] [Full Text] [PDF]
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 P J Mease Tumour necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors Ann Rheum Dis, April 1, 2002; 61(4): 298 - 304. [Abstract] [Full Text] [PDF]
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S. A. Schreyer, C. M. Vick, and R. C. LeBoeuf Loss of Lymphotoxin-alpha but Not Tumor Necrosis Factor-alpha Reduces Atherosclerosis in Mice J. Biol. Chem., March 29, 2002; 277(14): 12364 - 12368. [Abstract] [Full Text] [PDF]
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W. Pan, G. Cornelissen, F. Halberg, and A. J. Kastin Functional Genomics of Sleep and Circadian Rhythm: Selected Contribution: Circadian rhythm of tumor necrosis factor-alpha uptake into mouse spinal cord J Appl Physiol, March 1, 2002; 92(3): 1357 - 1362. [Abstract] [Full Text] [PDF]
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A. Wellmer, J. Gerber, J. Ragheb, G. Zysk, T. Kunst, A. Smirnov, W. Bruck, and R. Nau Effect of Deficiency of Tumor Necrosis Factor Alpha or Both of Its Receptors on Streptococcus pneumoniae Central Nervous System Infection and Peritonitis Infect. Immun., November 1, 2001; 69(11): 6881 - 6886. [Abstract] [Full Text] [PDF]
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 A. Oberholzer, C. Oberholzer, F.R. Bahjat, C. K. Edwards, and L. L. Moldawer Genetic determinants of lipopolysaccharide and D-galactosamine-mediated hepatocellular apoptosis and lethality Innate Immunity, October 1, 2001; 7(5): 375 - 380. [Abstract] [PDF]
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D.T. Graves, M. Oskoui, S. Voleinikova, G. Naguib, S. Cai, T. Desta, A. Kakouras, and Y. Jiang Tumor Necrosis Factor Modulates Fibroblast Apoptosis, PMN Recruitment, and Osteoclast Formation in Response to P. gingivalis Infection Journal of Dental Research, October 1, 2001; 80(10): 1875 - 1879. [Abstract] [PDF]
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