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Department of Veterinary Science and
Graduate Program in Biochemistry, Microbiology, and Molecular Biology, Pennsylvania State University, University Park, PA 16802
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and LPS by inhibiting the expression
of inducible NO synthase (iNOS). Furthermore, activated macrophages
from mice harboring targeted mutations in RON produce increased levels
of NO both in vitro and in vivo, rendering them more susceptible to
LPS-induced endotoxic shock. In this study, we demonstrate that
stimulation of murine peritoneal macrophages with MSP results in the
RON-dependent up-regulation of arginase, an enzyme associated with
alternative activation that competes with iNOS for the substrate
L-arginine, the products of which are involved in cell
proliferation and matrix synthesis. Expression of other genes
associated with alternative activation, including scavenger receptor A
and IL-1R antagonist, is also up-regulated in MSP-stimulated murine
macrophages. Stimulation of cells with IFN- and LPS blocks the
ability of MSP to induce arginase activity. However, pretreatment of
cells with MSP results in the up-regulation of arginase and inhibits
their ability to produce NO in response to IFN- and LPS, even in the
presence of excess substrate, suggesting that the inhibition of NO by
MSP occurs primarily through its ability to regulate iNOS
expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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While classically activated macrophages produce many inflammatory
mediators including NO, which exert microbicidal activities,
macrophages activated through the alternative pathway produce enhanced
levels of arginase. Arginase and inducible NO synthase
(iNOS),3 the enzyme
that produces NO, share a common substrate, L-arginine.
Metabolism of arginine through iNOS yields the products citrulline and
NO, while metabolism through arginase yields urea and ornithine. While
these enzymes catalyze the same substrate, their products have opposing
biological effects. NO is cytotoxic to microbes, parasites, and tumors,
and is generally antiproliferative. In contrast, ornithine is a
precursor for proline and polyamine synthesis, molecules that are
involved in cell growth and proliferation (4). Th2
cytokines, specifically IL-4 and IL-10, markedly down-regulate NO
production in macrophages, and it has been proposed that they do so by
the dual mechanism of suppressing the induction of iNOS gene expression
in response to proinflammatory mediators like IFN- and by enhancing
arginase activity, which reduces intracellular arginine accessible to
iNOS (5).
Recent data suggest that macrophage-stimulating protein (MSP) plays an important role in regulating the activities of macrophages during inflammation. MSP is an 80-kDa serum protein that was originally identified due to its ability to cause shape changes and induce responsiveness to chemoattractants in murine peritoneal macrophages (6, 7). MSP is most closely related to hepatocyte growth factor and belongs to a family of proteins characterized by a kringle domain and an inactive serine-protease-like domain (8). MSP is primarily produced in the liver as a biologically inactive single-chain pro-MSP (9) and can be converted to its active form by several coagulation cascade enzymes (10), a serine protease found in wound fluids (11), and a macrophage plasma membrane-associated enzyme (12). In primary murine peritoneal macrophages, MSP can both induce C5a-mediated chemotaxis and act as a chemoattractant itself (13). In these cells, MSP has also been shown to stimulate the phagocytosis of C3bi-coated SRBCs (14) and inhibit the production of NO by down-regulating the expression of iNOS in response to LPS (15).
The receptor for MSP is the RON receptor tyrosine kinase, a member of
the MET protooncogene family (16). RON was
originally isolated from a human keratinocyte cDNA library
(17), and the murine homolog, also called stem
cell-derived tyrosine kinase, was cloned from hemopoietic stem cells
(18). RON is a disulfide-linked heterodimer composed of an
extracellular 
-chain and a transmembrane 
-chain with intrinsic
kinase activity (19). Binding of MSP stimulates
autophosphorylation of two C-terminal tyrosine residues in the
multifunctional docking site (16). Signaling through this
family of receptors has been shown to recruit a number of Src homology
2-containing signaling molecules, including phospholipase C-,
phosphatidylinositol 3-kinase, Shc, and Grb2 (19, 20), as
well as the adaptor protein Gab 1 (21). The RON receptor
tyrosine kinase is not expressed on all populations of myeloid cells.
RON is expressed on resident peritoneal macrophages (22),
osteoclasts (23), and dermal macrophages
(11), but is not present on circulating monocytes or bone
marrow, spleen, and alveolar macrophages (22). RON
expression, which is regulated during inflammation, is inhibited by
proinflammatory cytokines (24) but is found up-regulated
on day 3 peritoneal exudate macrophages (22) and burn
wound exudate macrophages (11).
Activation of RON by MSP results in the inhibition of inducible NO
production by macrophages stimulated with LPS and inflammatory
cytokines such as IFN- and TNF- (15). This occurs
due to transcriptional repression of the iNOS gene, as shown in both
primary peritoneal macrophages (15) and RAW 264.7
macrophage-like cells (25). The inhibition of NO
production and iNOS requires the activation of phosphatidylinositol
3-kinase (25) and is associated with inhibition of IFN
regulatory factor-1 activity (26). Mice with a
targeted disruption in the RON gene demonstrate increased
susceptibility to LPS-induced septic shock, associated with increased
levels of serum NO due, at least in part, to increased production of NO
by RON-/- macrophages (27, 28). In
this study, we demonstrate that MSP can increase the expression and
activity of arginase as well as other markers of alternative
activation. In addition, the potential production of Th2 cytokines by
MSP was investigated.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mouse strains used for these experiments were CD-1, CD-1 mice with a targeted mutation in the RON gene (27), C57/B6, and C57/B6 mice with a deletion in the IL-10 gene (The Jackson Laboratory, Bar Harbor, ME). Murine resident peritoneal macrophages were obtained by peritoneal lavage with 10 ml of RPMI 1640 containing 10% FBS (Life Technologies, Gaithersburg, MD). Cells were incubated overnight and then washed with PBS to eliminate nonadherent cells. All cell cultures were maintained in RPMI 1640 plus 10% FBS at 37°C in a humidified incubator containing 5% CO2.
Reagents
MSP, IL-10, and IL-6 were obtained from R&D Systems
(Minneapolis, MN). IFN- was purchased from PeproTech (Rocky Hill,
NJ). LPS and L-arginine were obtained from Sigma-Aldrich
(St. Louis, MO).
Arginase and nitrite assays
Arginase activity was measured in cell lysates, as described by
Corraliza et al. (29), with modifications as described
previously (30). Briefly, cells were lysed with 100 µl
of 0.1% Triton X-100. After 30 min on a shaker, 100 µl of 25 mM
Tris-HCl was added. To 100 ml of this lysate, 10 µl of 10 mM
MnCl2 was added, and the enzyme was activated by
heating for 10 min at 55°C. Arginine hydrolysis was conducted by
incubating the lysates with 100 µl of 0.5 M L-arginine
(pH 9.7) at 37°C for 60 min. The reaction was stopped with 800 µl
of H2SO4
(96%)/H3PO4
(85%)/H2O (1/3/7, v/v/v). The urea concentration
was measured at 550 nm after addition of 40 µl of
-isonitrosopropiophenone (Sigma-Aldrich) (dissolved in 100%
ethanol), followed by heating at 100°C for 30 min. One unit of enzyme
activity is defined as the amount of enzyme that catalyzes the
formation of 1 µmol urea/min.
To determine the levels of NO production, macrophages were plated in a 96-well plate at a concentration of 1 x 105 cells/well. Following stimulation, the production of NO was determined by assaying culture supernatants for NO2-, a stable reaction product of NO with molecular oxygen. Briefly, 100 ml of culture supernatant was reacted with an equal volume of reagent (1% sulfanilamide/0.1% naphthylethylene diamine dihydrochloride/2.5% H3PO4) at room temperature for 10 min, after which the absorbance at 550 nm was determined.
RNA extraction and RT-PCR
Arginase, IL-10, IL-6, and IL-1R antagonist (IL-1Ra) expression in resting and MSP-activated resident peritoneal macrophages was analyzed by RT-PCR. Briefly, 1 x 106 cells were activated with 100 ng/ml MSP for 24 h, after which they were harvested for RNA isolation using the guanidinium thiocyanate method. Reverse transcription was conducted for 15 min at 42°C using random hexamers from 0.3 µg of total RNA. Conditions for arginine I and II PCR are as follows, as described previously (30): 95°C for 5 min, followed by 35 cycles of 20 s at 95°C, 20 s at 56°C, and 30 s at 72°C, with a final extension at 72°C for 10 min. The sequences of primers used are: arginine I sense, 5'-CAGAAGAATGGAAGAGTCAG-3', and antisense, 5'-CAGATATGCAGGGAGTCACC-3'; and arginine II sense, 5'-TGATTGGCAAAAGGCAGAGG-3', and antisense, 5'-CTAGGAGTAGGAAGGTGGTC-3'. The conditions for IL-1Ra are as follows, as described previously (31): 99°C for 5 min followed by 30 cycles of 94°C for 45 s, 54°C for 45 s, and 72°C for 60 s, with a final extension at 72°C for 5 min. The sequences of primers used are: sense, 5'-CCCTTCTGGGAAAAGACCCTGCAAG-3', and antisense, 5'-GAACTTCGTGACTATAAGGGGCTC-3'. The conditions for IL-6 and IL-10 are as follows, as described previously (32): 95°C for 5 min followed by 30 cycles of 95°C for 15 s, 58°C for 20 s, and 72°C for 30 s, with a final extension at 72°C for 6 min. The sequences of primers used are: IL-6 sense, 5'-CAGAAAGCCAGAGTCCTTCAGAGAG-3', and IL-6 antisense, 5'-CTAGGTTTGCCGACTAGATCTC; IL-10 sense, 5'-CTGAGGCGCTGTCATCGATT-3', and IL-10 antisense, 5'-AGGTCCTGGAGTCCAGCAGA-3'. PCR products were run on a 1% agarose gel.
Western blot analysis
A total of 1 x 107 cells was incubated in the presence or absence of 300 ng/ml MSP for 24 h. After incubation, cells were harvested with a cell scraper, washed with PBS, pelleted, and lysed for 15 min on ice in 500 µl of lysis buffer containing 150 mM NaCl, 10 mM Tris-HCl (pH 7.5), 0.5% Triton X-100, and protease inhibitors 1 µg/ml leupeptin, 1 µg/ml pepstain A, and 2 µg/ml aprotinin. The protein contents were determined using the dendritic cell protein assay kit (Bio-Rad, Richmond, CA). Absorbance was measured at 750 nm with a Beckman DU530 spectrophotometer (Beckman Coulter, Palo Alto, CA). Proteins were mixed with 5x SDS sample buffer, SDS-PAGE, using 12.5% bis-acrylamide gel for separation, which was performed with a MiniProtean II Cell (Bio-Rad) at 65 V for 15 min, then at 150–160 V for 1 h. Immobilon P polyvinylidene difluoride membranes (Millipore, Bedford, MA) were washed briefly in methanol and then ddH2O, then equilibrated in trans-blotting buffer (48 mM Tris, 39 mM glycine, and 20% methanol) for 5 min. The gels were washed in ddH2O, then in trans-blotting buffer for 15 min. Trans-blotting was performed using the Mini Trans-Blot Electrophoretic Transfer Cell (Bio-Rad) for 1 h at 100 V. The blots were then placed in blocking buffer containing 5% nonfat dry milk for 1 h at room temperature. The blots were then incubated overnight at 4°C with mouse anti-rat arginase I Ab (Transduction Laboratories, Lexington, KY), according to manufacturer’s instructions, followed by anti-mouse peroxidase-conjugated secondary Ab. Protein was then detected by incubating the blots in chemiluminescence substrates (Amersham, Piscataway, NJ) and exposing to x-ray film.
Flow cytometry
Cells were harvested, incubated in the presence or absence of
100 ng/ml MSP for 24 h, and washed with PBS. A total of 5 x
105 cells/100 µl was resuspended in PBS plus
2% newborn calf serum on ice. FcR were blocked using 1 µl of
anti-mouse CD32/16 (FcIII/IIR; BD PharMingen, San Diego, CA) for
5 min on ice. Scavenger receptor A (SR-A) expression was
detected using a FITC-conjugated rat anti-mouse macrophage
scavenger receptor Ab (Serotec, Oxford, U.K.) and analyzed by flow
cytometry (XL; Coulter, Hialeah, FL).
AcLDL endocytosis assay
Cells were harvested, incubated in the presence or absence of 100 ng/ml MSP and 5 ng/ml IL-10 for 24 h, and washed with PBS. A total of 5 x 105 cells was then incubated with 2 µg/ml 1,1'-dioctadecyl-1-3,3,3',3'-tetramethylindocyanine (DiI)-acetylated low density lipoprotein (AcLDL; Intracel, Rockville, MD) for 4 h in serum-free RPMI plus 2 mg/ml BSA. Cells were then washed with PBS, harvested in PBS plus 2% newborn calf serum, and analyzed by flow cytometry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previously, we and others have shown that the MSP/RON signaling
pathway inhibits NO production in response to IFN- and LPS
(25, 26). We have also seen that MSP can inhibit the
up-regulation of iNOS gene in response to IFN- and LPS in resident
peritoneal macrophages (data not shown), as seen previously by Wang et
al. (15). Several Th2 cytokines, including IL-4 and IL-10,
that inhibit NO production by activated macrophages also up-regulate
expression of arginase, which competes with iNOS for the substrate,
L-arginine. To determine whether MSP can induce arginase
activity, resident peritoneal macrophages were incubated with MSP for
24 h, and arginase activity was measured. MSP stimulation
consistently increased arginase activity approximately 2- to 3-fold
(Fig. 1
A). To determine
whether the up-regulation of arginase by MSP is mediated by the RON
receptor, macrophages from RON-deficient mice were utilized (Fig. 1B). MSP was unable to induce arginase activity in
RON-deficient macrophages, suggesting that the observed increase in
arginase activity in response to MSP is mediated by the RON receptor.
Although RON-deficient macrophages did not show increased arginase
activity in response to MSP, these cells were capable of up-regulating
arginase activity in response to the Th2 cytokine IL-4 (Fig. 1C).
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A). The
induction of arginase activity in response to MSP appears to be
primarily due to an increase in arginase I expression. These results
were confirmed by quantitative real time RT-PCR. In addition, arginase
I protein was induced by MSP stimulation, as shown by Western blot
analysis (Fig. 2B).
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Up-regulation of arginase activity in macrophages is an event
associated with alternative activation. Therefore, we set out to
determine whether the expression of other genes associated with
alternative activation of macrophages was also up-regulated in response
to MSP. While classically activated macrophages primarily express IgG
receptors, alternatively activated macrophages express a variety of
immune pattern recognition receptors such as the mannose receptor
(2), the -glucan receptor (33), and the
scavenger receptor type I (34), which give these cells
enhanced phagocytic ability by recognizing a wide variety of foreign
Ags. SR-A plays a role in binding and endocytosis of AcLDL and oxidized
LDL, phagocytosis of apoptotic cells, cell adhesion, and host defense
function (reviewed in Ref. 35). SR-A expression on
macrophages is up-regulated following differentiation from monocytes to
macrophages; however, stimulation with MSP for 24 h resulted in
increased expression of this receptor, as seen by flow cytometry (Fig. 3A). This observed increase in
expression was mediated by the RON receptor, as macrophages
from RON-deficient mice did not show an increase in SR-A expression in
response to MSP (data not shown). Expression of CD-11b, a marker of
macrophage differentiation, remained unchanged in these cells when
stimulated with MSP (data not shown). In addition to increased
expression of SR-A, we also observe an increase in the number of
macrophages able to endocytose DiI-labeled AcLDL when stimulated with
MSP, as measured by flow cytometry (Fig. 3C).
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alternatively activated macrophages preferentially express cytokines
with anti-inflammatory effects, such as IL-1Ra (36)
and IL-10. IL-1Ra inhibits the action of IL-1 and IL-1 by
competitively binding to IL-1Rs but has no agonist activity (reviewed
in Ref. 37). To determine whether MSP induced IL-1Ra
expression in primary peritoneal macrophages, we analyzed IL-1Ra RNA
expression by RT-PCR. Our results demonstrate that IL-1Ra RNA
expression was consistently induced by MSP stimulation (Fig. 3
B). MSP-induced arginase activity and SR-A expression are independent of IL-10 production
Arginase has previously been shown to be induced by stimulation of
macrophages with IL-4 and IL-10 (38). While IL-4 is
primarily produced by T-cells, IL-10 can be produced by macrophages.
LPS has also been shown to induce arginase activity, but recent results
suggest that this induction is mediated by the ability of LPS to induce
IL-10 production by macrophages (30). In addition, IL-10
is also considered a marker of alternative activation (3).
To elucidate the mechanism by which MSP induces arginase activity, we
wanted to determine whether MSP induces production of cytokines known
to stimulate this activity. To determine whether MSP-induced arginase
activity is dependent on IL-10 production, macrophages were isolated
from mice with a targeted mutation in the IL-10 gene. When these
macrophages were stimulated with MSP, the levels of arginase activity
were similar to those seen in wild-type macrophages (Fig. 4A). Similarly, SR-A
expression on IL-10 knockout macrophages is also induced by MSP at
levels comparable with those seen in wild-type macrophages (Fig. 4B). We also analyzed RNA from macrophages stimulated with
MSP for 24 h and saw no observable increase in IL-10 expression
(Fig. 4D). There was also no increase in IL-10 production
from MSP-stimulated cells, as determined by ELISA (data not shown).
Therefore, the ability of MSP to induce arginase activity and SR-A
expression is independent of IL-10.
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sites in the
arginase I promoter (39). IL-6 stimulation (10 ng/ml) of
murine resident peritoneal macrophages for 24 h showed a similar
2- to 3-fold increase in arginase activity as seen with MSP (Fig. 4C); however, RNA analyzed by RT-PCR from MSP-stimulated
macrophages did not reveal any IL-6 expression in these cells (Fig. 4D). Antagonistic production of NO and arginase in response to proinflammatory cytokines and MSP
We and others have shown previously that expression of the RON
receptor in RAW 264.7 cells results in a decrease in the
transcriptional activation of iNOS in response to cytokine
stimulation(25, 26). To determine whether the
ability of MSP to inhibit NO production is also due to its ability to
up-regulate arginase activity and compete with iNOS for the substrate,
L-arginine, we stimulated murine peritoneal macrophages
with IFN- and LPS in the presence and absence of MSP for 24 h
and measured arginase activity and NO production (Fig. 5). MSP was able to inhibit NO production
in response to IFN- and LPS, as previously reported
(15); however, in these cells, MSP failed to enhance
arginase activity. However, pretreatment of macrophages for 9 h
with MSP before stimulation with IFN- and LPS enhanced arginase
activity and resulted in an even larger decrease in NO production (Fig. 5, A and B). Macrophages prestimulated with MSP
were refractory to IFN- and LPS treatment even in the absence of
additional MSP. The addition of excess arginine (Fig. 5, C
and D) did not affect the ability of MSP to inhibit NO
production. Similar results were seen with up to 12 mM exogenous
arginine (data not shown). These data suggest that the ability of MSP
to inhibit NO production in response to IFN- and LPS under these
conditions is not due to competition for substrate by arginase. In a
larger context, these studies demonstrate that Th1 cytokines and MSP
act in an antagonistic manner in their ability to stimulate macrophages
to produce NO and increase arginase activity, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-activated
macrophages, MSP can also induce arginase activity. This increase in
arginase activity is a result of an increase in arginase RNA and
protein expression. Arginase activity is a marker of alternative
activation in macrophages. Other markers, such as SR-A and IL-1Ra, also
appear up-regulated by MSP stimulation. Taken together, these results
suggest that MSP may play a role in the alternative activation process.
While it remains speculative, the ability of MSP to induce genes
associated with alternative activation in macrophages may play a role
in its ability to regulate septic shock.
Activation of arginase has also been shown to play an important role in
helping to alleviate endotoxic shock. NO production by macrophages is
dependent on an extracellular level of L-arginine
(40), and arginase can decrease NO production by reducing
L-arginine availability to iNOS (41).
Intravenously added arginase has also been shown to decrease NO
formation in the liver, lung, spleen, and kidney in LPS-treated rats as
well as plasma nitrite levels (42). However, in the
studies described in this work, the addition of excess arginine did not
overcome the ability of MSP to inhibit NO production. While MSP is able
to activate arginase expression, it also directly inhibits the
transcription of iNOS in response to IFN- and LPS. Therefore, it
appears that the iNOS and arginase signaling pathways may be
independent targets of MSP. Preliminary data from our lab have
suggested that different mitogen-activated protein kinases (MAPKs) may
be required for the regulation of arginase and iNOS. We have seen that
chemical inhibitors of p38 MAPK can inhibit arginase induction, but
have no effect on NO production. Recent work has also shown that p38
MAPK and cAMP/protein kinase A are required for IL-13-induced arginase
activity (43). On the other hand, chemical inhibitors of
mitogen-activated protein/extracellular signal-related kinase kinase
can inhibit the ability of MSP to inhibit NO production, but have no
effect on the ability of MSP to induce arginase.
A role for SR-A in protection against endotoxic shock has also been demonstrated. Mice with a targeted mutation in the gene encoding SR-A are more sensitive to endotoxic shock and are more susceptible to infection with Listeria monocytogenes (44), both phenotypes that were also observed in the RON-deficient mice (27, 51). It has been suggested that the SR-A knockout mice may be more susceptible to endotoxic shock due to the ability of the SR-A to act as an alternate binding site for LPS and quench excess endotoxin away from CD-14 (45). Studies in transgenic and knockout mice also indicate that IL-1Ra is important for protection from endotoxin-induced sepsis (46). In vivo studies have shown that treatment with rIL-1Ra reduces the severity of experimental sepsis, chemically induced colitis, arthritis, and diabetes (37). The ability of MSP to up-regulate both SR-A and IL-1Ra may also prove important in protection from endotoxic shock.
Experimental evidence has suggested that RON/MSP may also play a role in wound healing. Previous studies have shown increased levels of active MSP in human burn wound fluid, as well as the up-regulation of RON on keratinocytes and dermal macrophages at wound sites (11). In experimental rat wounds, decreased levels of arginine in the wound fluid were accompanied by increased levels of ornithine and high arginase activity (47). It has been suggested that the cellular localization of the arginase isoforms dictates their functions. Ornithine decarboxylase, like arginase type I, is located in the cytosol and utilizes ornithine in the production of polyamines (48). In contrast, ornithine aminotransferase, the enzyme that initiates the conversion of ornithine to proline, which is essential for collagen synthesis, is located within the mitochondria (4). The production of both polyamines and collagen is important in the healing wound. The ability of MSP to induce expression of arginase I provides further evidence to suggest that this pathway may play an important role in wound healing.
While cytokines such as IL-10 and IL-6 can induce arginase activity,
results demonstrated in this work show that MSP-induced arginase
activity is not dependent on IL-10 or IL-6 production. However, IL-10,
IL-6, and MSP appear to induce arginase activity to similar levels. One
downstream signaling pathway shared by these diverse receptors is the
activation of STAT3. STAT3 has been shown to be downstream of c-Met
receptor signaling (49). Conditional macrophage knockouts
of STAT3 have defects in their inflammatory response, similar to
defects seen in both the RON- and IL-10-deficient mice. STAT3
macrophage knockouts are highly susceptible to endotoxic shock and show
increased production of inflammatory cytokines such as TNF-,
IFN-, and IL-1 (50). It will be of interest to
determine whether these macrophages are defective in their ability to
up-regulate arginase activity in response to IL-10, IL-6, or
MSP.
Much like the dichotomy found in Th cells, macrophages are activated
down two distinct pathways. The regulation of RON may play an important
role in this balanced macrophage activation. The inability of MSP to
induce arginase activity when cells were stimulated simultaneously with
IFN- and LPS may result from the suppressive effects of these
inflammatory cytokines on RON expression. Based on the data presented
in this work, we suggest a model in which down-regulation of RON by
inflammatory cytokines during the initial stages of an immune response
may enhance classical activation, while its up-regulation during later
stages of an immune response and in wounds may facilitate alternative
activation and promote healing.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Pamela H. Correll, Department of Veterinary Science, 115 Henning, Pennsylvania State University, University Park, PA 16802. E-mail address: phc7{at}psu.edu
3 Abbreviations used in this paper: iNOS, inducible NO synthase; LDL, low density lipoprotein; AcLDL, acetylated LDL; IL-1Ra, IL-1R antagonist; MAPK, mitogen-activated protein kinase; MSP, macrophage-stimulating protein; SR-A, scavenger receptor A; DiI, 1,1'-dioctadecyl-1,3,3,3',3'-tetramethylindocyanine.
Received for publication April 27, 2001. Accepted for publication November 2, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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P. Kalantari, O. F. Harandi, P. A. Hankey, and A. J. Henderson HIV-1 Tat Mediates Degradation of RON Receptor Tyrosine Kinase, a Regulator of Inflammation J. Immunol., July 15, 2008; 181(2): 1548 - 1555. [Abstract] [Full Text] [PDF]
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X. Wei, S. Ni, and P. H. Correll Uncoupling Ligand-dependent and -independent Mechanisms for Mitogen-activated Protein Kinase Activation by the Murine Ron Receptor Tyrosine Kinase J. Biol. Chem., October 21, 2005; 280(42): 35098 - 35107. [Abstract] [Full Text] [PDF]
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E. S. Lee, P. Kalantari, S. Tsutsui{section}, A. Klatt, J. Holden, P. H. Correll, C. Power{section}, and A. J. Henderson RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, Inhibits HIV-1 Transcription in Monocytes/Macrophages and Is Decreased in Brain Tissue from Patients with AIDS J. Immunol., December 1, 2004; 173(11): 6864 - 6872. [Abstract] [Full Text] [PDF]
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A. C. Morrison, C. B. Wilson, M. Ray, and P. H. Correll Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-{gamma} and Lipopolysaccharide J. Immunol., February 1, 2004; 172(3): 1825 - 1832. [Abstract] [Full Text] [PDF]
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 M. C. Rodriguez-Galan, C. Sotomayor, M. E. Costamagna, A. M. Cabanillas, B. S. Renteria, A. M. Masini-Repiso, and S. Correa Immunocompetence of macrophages in rats exposed to Candida albicans infection and stress Am J Physiol Cell Physiol, January 1, 2003; 284(1): C111 - C118. [Abstract] [Full Text] [PDF]
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