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*
Cellular and Molecular Immunology Group, Antigenics, Inc., Woburn, MA 01801; and
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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; stimulation of macrophages with
mixtures of IFN- and gp96 or hsp70 leads to a synergistic production
of NO. The present observations extend the roles of these heat shock
proteins in innate immune responses to another potent and highly
conserved function of APC. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-12, IL-1
, and GM-CSF and
the up-regulation of Ag-presenting and costimulatory molecules such as
MHC II and CD86 (12, 13, 14, 15). This latter phenomenon is
independent of antigenic context. The highly abundant HSPs are released
upon necrotic, but not apoptotic, cell death, and the proinflammatory
activity of HSPs may constitute a mechanism for the immune system to
perceive necrotic events, putting it in a state of molecular alert to
be able to respond to simultaneous antigenic context
(12). In the present study, we show that interaction of HSPs gp96 and hsp70 with APCs results in a potent and highly conserved immunological phenomenon, i.e., production of NO by APCs. The release of NO by monocytes exposed to hsp60 has been documented previously (15). HSPs gp96 and hsp70 stimulate murine and human macrophage and dendritic cells (DC) to induce the expression of inducible NO synthase (iNOS) and the consequent production of NO. This aspect of HSP-APC interaction is yet another example of the increasingly emergent pattern in which HSPs function as the mammalian body’s internal agents for activation of APCs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The RAW264.7 cell line (ATCC TIB-71) and U937 cells (ATCC CRL
1593.2) were obtained from American Type Culture Collection (Manassas,
VA). Cell lines were maintained in DMEM (Life Technologies,
Gaithersburg, MD) supplemented with 10% FCS (HyClone, Logan, UT), 1 mM
sodium pyruvate, 2 mM L-glutamine, 100 U/ml penicillin, and
100 µg/ml streptomycin (Life Technologies) at 37°C in 5%
CO2. N-monomethyl arginine (N-MMA),
Escherichia coli 0128 strain LPS, BSA, and PMA were
purchased from Sigma-Aldrich (St. Louis, MO). Murine recombinant
IFN- and human recombinant IFN- were purchased from Calbiochem
(La Jolla, CA) and Pierce-Endogen (Woburn, MA), respectively. U937
monocyte cells were differentiated into macrophage stage cells by
treatment with PMA at 25 ng/ml for 72 h at 37°C in 5%
CO2. Macrophage stage cells were harvested by
trypsinization and washed to remove PMA before assay. Differentiation
was confirmed by adherence phenotype and up-regulation of CD36
differentiation marker (16) using FA6.152 anti-human
CD36 mAb (Immunotech, Marseilles, France).
Purification of HSPs, testing for LPS and FITC conjugation
gp96 and hsp70 were prepared from pooled livers and kidneys of C57BL/6 mice as previously described (17). All glassware used in HSP preparation was previously depyrogenated. The LPS content of preparations was assayed using the Limulus amebocyte lysate assay kit (BioWhittaker, Walkersville, MD). gp96, hsp70, and histone (type III-SS; Sigma-Aldrich) were conjugated with FITC using the FluoroTag kit (Sigma) according to the manufacturer’s protocol, using a 20:1 FITC monomer:protein molar ratio.
Preparation of bone marrow dendritic cells (BMDC)
BMDC were generated as previously described (18). Briefly, femurs from 8- to 12-wk-old female C57BL/6 mice were flushed, and the bone marrow cells recovered were incubated with 20 ng/ml GM-CSF (Pierce-Endogen for 6 days, followed by transfer of loosely adherent cells to fresh plates and recovery of nonadherent cells on day 7. This population was highly enriched for CD11c+ cells as determined by FACS analysis. Mature DC were prepared by the addition of 100 ng/ml LPS to the freshly transferred day 6 culture described above, followed by recovery of nonadherent cells on day 7. LPS was removed by washing mature DCs before assay.
Preparation of primary peritoneal macrophages
Female C57BL/6 mice (8–12 wk old) were injected i.p. with 0.2 ml Pristane (Sigma-Aldrich). Peritoneal exudate cells were recovered 5 days postinjection by peritoneal lavage with DMEM. Peritoneal macrophages were purified by adherence to plastic for 4 h before assay.
Assay for NO
RAW264.7, macrophage or monocyte stage U937 cells, or adherence-purified peritoneal macrophages were incubated at 1 x 105 cells/well in 96-well plates along with increasing quantities of gp96, hsp70, or control stimuli as indicated in DMEM (Life Technologies) supplemented with 10% FCS (HyClone), 1 mM sodium pyruvate, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin (Life Technologies) for 24 h at 37°C in 5% CO2. Cell-free supernatants were recovered after incubation, and NO production was analyzed as NO3- and NO2- concentrations using an enzymatic colorimetric NO assay (Oxford Biomedical, Oxford, MI) according to the manufacturer’s protocol.
Immunoblotting for iNOS
Adherence-purified peritoneal macrophages were stimulated with
gp96 and control stimuli as indicated for 24 h at 37°C in 5%
CO2. Stimulated cells were lysed in 1% Triton
X-100 containing lysis buffer supplemented with 200 µM PMSF, 5 µM
leupeptin, and 10 µM E64 protease inhibitors. Lysates were separated
by SDS-PAGE, followed by immunoblotting with rabbit anti-mouse iNOS
polyclonal Ab (Calbiochem). The blot was stripped and reprobed with an
anti-mouse -actin mAb to ascertain equal loading of all
lanes.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Homogenous preparations of the HSPs gp96 and hsp70 were purified
from the livers and kidneys of C57BL/6 mice under near-GMP conditions.
RAW264.7 cells (d haplotype) of murine macrophage origin
were incubated with increasing quantities of gp96 or hsp70, or with LPS
as a positive control. NO was produced in response to stimulation with
either HSP in a dose-dependent manner (Fig. 1
A) and upon stimulation with
LPS (Fig. 1B). The generation of NO via iNOS has been shown
previously to be inhibited by the L-arginine
analog N-MMA (19). The production of NO induced by gp96,
hsp70, or LPS was also inhibited by N-MMA (Fig. 1A). NO
generation was not elicited by an irrelevant protein such as BSA at
comparable protein concentrations.
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C). All HSP preparations were tested for LPS content
by Limulus amebocyte lysate assay and were found to have no
detectable LPS up to the sensitivity limits of the assay (
0.01
endotoxin U/ml). Heat denaturation of HSPs abolished the ability of HSP
to elicit NO production (85% inhibition); heat denaturation of
LPS had no effect on its ability to elicit NO production. RSLP,
a component derived from Rhodopseudomonas spheroids
(20), has been shown to be a competitive inhibitor of LPS.
RSLP significantly inhibited LPS-elicited NO production (75%
inhibition), but did not have a significant effect on gp96-induced NO
release (7% inhibition; Fig. 1C). RSLP did cause
significant, but limited, inhibition of hsp70-elicited NO production.
Approximately 50% activity of hsp70 was retained in the presence of
RSLP; this was not the case with LPS. Also, in this particular assay
the inhibition by RSLP was tested at a high hsp70 concentration; at
lower concentrations, RSLP inhibited the activity of hsp70 more
modestly (data are not shown, as they were parts of other experiments).
The abrogation of the activity of hsp70, but not LPS, by boiling also
substantiates the lack of contribution of LPS in the activity of
hsp70.
The ability of primary macrophages to release NO in response to HSPs
was evaluated. Pristane-induced, adherence-purified, primary mouse
peritoneal macrophages were incubated with increasing quantities of the
HSPs gp96 and hsp70. As with the mouse macrophage cell line
RAW264.7, a dose-dependent, N-MMA-sensitive induction of NO output was
observed with gp96 or hsp70 (Fig. 1D). LPS also induced NO
release from primary cells (Fig. 1E).
Human myeloid U937 cells were tested for their ability to generate NO
in response to HSP stimulation. The nonadherent human monocyte cell
line U937 can be differentiated to an adherent macrophage-like state by
treatment with PMA (21), with a concomitant increase in
the expression of HLA-DR, CD36, and the macrophage marker CD11b
(16, 22, 23). U937 monocyte cells were induced to
differentiate into the macrophage stage by addition of PMA, and
differentiation was monitored by increased expression of CD36 (Fig. 2A). Equal numbers of
PMA-treated U937 macrophages or untreated U937 monocytes were incubated
with increasing quantities of gp96, hsp70, or LPS. gp96 and hsp70
induced a dose-dependent increase in NO output in both macrophage and
monocyte stage U937 cells (Fig. 2B); however, the production
of NO was markedly greater from macrophage stage cells in the case of
both HSPs. In contrast, the macrophage and monocytic stages of U937
responded equally effectively to LPS (Fig. 2C).
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B gave rise to the possibility
that the differences in response of macrophage stage and monocytic
stage U937 myeloid cells to HSP stimulation result from quantitative
differences in cell surface binding of HSPs by the two cell types.
However, FACS analysis of gp96-FITC binding showed no increase in the
ability of macrophage stage cells to bind gp96 or hsp70 relative to
monocyte stage cells (Fig. 2D), suggesting that differences
in downstream signaling events between the two cell types might instead
be responsible. gp96-APC interaction induces iNOS
HSP-stimulated induction of the enzyme responsible for NO
production by mouse macrophages was studied at the protein level.
Primary mouse macrophages were incubated for 24 h with LPS, BSA,
or gp96 at the concentrations indicated or in medium alone. Treated
cells were lysed and subjected to SDS-PAGE, immunoblotting, and probing
with an anti-mouse iNOS polyclonal Ab (see Materials and
Methods). Induction of iNOS protein was observed in cells
stimulated with LPS or gp96, but not in those stimulated with
comparable quantities of BSA or in cells incubated with medium alone
(Fig. 3). Immunoblotting of the same
extracts, performed with a mAb to -actin, confirmed that cell
lysates from equivalent numbers of cells were applied to each
lane.
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The ability of BMDCs to produce NO in response to stimulation with
gp96 was tested. Nonmatured BMDCs as well as BMDCs that had been
exposed to LPS as a maturation signal and thus expressed high levels of
MHC II (Fig. 4A) were used in
such assays. In nonmatured BMDCs, gp96, but not BSA, stimulated NO
release in a dose-dependent, N-MMA-sensitive fashion (Fig. 4B). The LPS-matured BMDCs, on the other hand, showed a high
level of N-MMA-sensitive NO release even without stimulation with gp96.
Exposing them to gp96 did not further enhance this level of NO release
(Fig. 4B). Similar to the data shown in Fig. 1C,
heat-denatured gp96 did not stimulate nonmatured or LPS-matured
BMDCs to produce NO; heat-treated LPS was still active in the same
assay (Fig. 4C).
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on NO release by APCs
IFN- is known to be an inducer of NO production in macrophages
and synergizes with cytokine stimuli such as TNF- and CD40 ligand in
this function (24, 25). The effect of HSPs on the release
of NO by primary macrophage in concert with IFN- was examined (Fig. 5). It was observed that 1) activation of
mouse peritoneal macrophages with gp96, hsp70, or IFN- resulted in
the release of NO; 2) stimulation with gp96 and IFN- caused a level
of NO release that exceeds the sum of the levels of NO released by
either agent alone (Fig. 5A); 3) stimulation with hsp70 and
IFN- caused a level of NO release that exceeds the sum of the levels
of NO released by either agent alone (Fig. 5B); and 4)
stimulation with gp96 and hsp70 caused a level of NO release that was
synergistic to the sum of the levels of NO released by either agent
alone (Fig. 5C). Thus, the two HSPs tested not only
synergize with IFN-, but also with each other in the stimulation of
macrophage NO release. A similar effect was observed with LPS and
IFN-, as has been reported previously (19) (Fig. 5D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, endotoxin, TNF- (19),
and ligation of CD40 (25, 26). DCs produce NO in response
to similar stimuli (27, 28). In addition to production of
TNF-, production of NO has been shown to be a major
tumoricidal mechanism of activated macrophages in vitro
(29, 30, 31) and in vivo (32, 33). A number of
tumor immunotherapeutic protocols can be ablated by pharmacological
interference with NO production (34, 35). Macrophage NO
production has also been shown to be critical for the control of
microbial pathogens such as Leishmania major (36, 37) and Staphylococcus aureus (38) and
viral pathogens such as HSV-1 (39).
NO production is also an immunomodulator of Th cell function. This
control is exercised through direct cytostatic and proapoptotic effects
of NO, which appear selective for Th1 cells (40, 41), as
well as regulation of the agonist (p35)/antagonist (p40) forms
(42) of macrophage IL-12 (43, 44, 45, 46) and T cell
cytokines (47). Regulation of IL-12 agonism also affects
Th1 function preferentially, since IL-12 is an inducer of the
expression of the Th1 effector cytokine IFN-. Such
immunomodulatory activity may serve to limit potentially dangerous
local cellular immune responses.
We show here that the interaction of the HSPs gp96 and hsp70 with a variety of murine and human APCs and APC cell lines results in the induction of iNOS and the release of NO. HSP-APC interaction has been shown previously to result in the secretion of an array of inflammatory cytokines by macrophages and maturation of DCs (12, 13, 14, 15). The results shown here extend that paradigm and add to it in three novel ways. First, they identify NO secretion as a novel consequence of interaction of gp96 and hsp70 with APCs. Interaction of human hsp60 with human monocytes, leading to NO release, has been reported previously (15). Second, our results identify the differentiation status of APCs as being determinative of the NO response upon encounter with HSPs. In the case of monocyte-macrophage differentiation, the macrophage are more responsive to gp96 or hsp70 than the monocytes. This is not due to quantitative differences in the engagement of a gp96 or hsp70 receptor by either cell type, as both cell types bind comparable quantities of the HSPs. The differences may derive from other factors, such as activation status and signaling components of the two cell types. It is also noteworthy that the macrophage and monocytes respond differentially to HSPs, but not to LPS, suggesting that HSPs and LPS signal through different receptors. Third, our results show that the nonmatured and mature DCs differ markedly in NO production. Nonmatured DCs release little, if any, NO under unstimulated conditions, whereas LPS-matured DCs produce high levels of NO under the same conditions. Gp96 induces nonmatured, but not LPS-matured, DCs to liberate NO.
The production of NO by HSP-activated APC is likely to have a consequence for the innate control of tumors and infectious diseases. APCs patrolling interstitial spaces where necrosis of hypoxic or nutrient-starved tumor cores or lysis of infected cells by cytopathic pathogens have occurred would encounter released HSPs. In addition to providing antigenic information to initiate an effector T cell response against the antigenic context provided, control of the target tumor or infected tissue in this case could be further potentiated by the cytotoxic contribution of NO-producing macrophages that have arisen in proximity to CTL-targeted, HSP-releasing necrotic tissue.
NO release by HSP-activated APC may also provide a layer of
immunomodulation of Th cells by necrosis-released HSP. Whereas lower
levels of NO are cytoprotective (by inactivation of proapoptotic
proteases and up-regulation of Bcl-2) (48, 49, 50), higher
levels are cytotoxic to T cells, particularly Th1 cells (40, 41, 51). In the case of HSP released from damaged tissue, the
concurrent danger of a deleterious immune response being mounted to
self-Ags could be prevented by the coinduction of high levels of NO by
IFN- and HSP, leading to the death of T cells. The context of the
IFN- produced by infiltrating, autoreactive Th1 cells would
therefore be modified away from its usual effector functions by the
presence of released HSP and would instead result in NO-mediated Th1
suppression by alteration of the IL-12 p35/p40 balance and direct
selective cytotoxic elimination of Th1 cells. This may constitute an
ongoing innate mechanism for the avoidance of T cell autoreactivity and
autoimmune disease. The involvement of NO in autoimmune disease remains
unclear. Interference with NO production in vivo in various models of
autoimmune disease has resulted in amelioration or exacerbation of
disease (reviewed in Ref. 52). It is possible that the
former is a result of prevention of destruction of normal tissues by
the cytotoxic actions of NO, whereas the latter may be the result of
lifting of immunomodulatory control of potentially destructive T cell
activity.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Pramod K. Srivastava, University of Connecticut School of Medicine, MC1601, Farmington, CT 06030-1601. E-mail address: srivastava{at}nso2.uchc.edu
3 Abbreviations used in this paper: HSP, heat shock protein; DC, dendritic cell; BMDC, bone marrow-derived DC; iNOS, inducible NO synthase; N-MMA, N-monomethyl arginine.
Received for publication August 6, 2001. Accepted for publication January 8, 2002.
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L. A. E. Harmala, E. G. Ingulli, J. M. Curtsinger, M. M. Lucido, C. S. Schmidt, B. J. Weigel, B. R. Blazar, M. F. Mescher, and C. A. Pennell The Adjuvant Effects of Mycobacterium tuberculosis Heat Shock Protein 70 Result from the Rapid and Prolonged Activation of Antigen-Specific CD8+ T Cells In Vivo J. Immunol., November 15, 2002; 169(10): 5622 - 5629. [Abstract] [Full Text] [PDF]
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