Download RECEPTOR TYROSINE KINASES AND THE REGULATION OF

RECEPTOR TYROSINE KINASES AND THE REGULATION
OF MACROPHAGE ACTIVATION
Correll PH, Morrison AC and Lutz MA
Department of Veterinary Science
The Pennsylvania State University
University Park, PA 16802
Corresponding Author:
Pamela H. Correll
Department of Veterinary Science
115 Henning Building
The Pennsylvania State University
University Park, PA 16802-3500
Phone: 814-863-0128
FAX: 814-863-6140
Email: [email protected]
Running Title: RTK activation of macrophages
Key Words: Receptor tyrosine kinase, macrophage activation, STK/RON,
Mer/Axl/Tyro3
It is becoming increasingly clear that macrophages are a diverse and dynamic population
of cells that can be activated down a number of distinct developmental pathways (recently
reviewed in [1, 2]). These cells have the capacity to perform a wide range of critical functions
including; 1) the recognition, phagocytosis and clearance of invading pathogens through the
expression of pattern recognition receptors (PRRs) and the upregulation of cytotoxic molecules,
2) immune modulation through the production of cytokines and chemokines, antigen presentation
the regulation of T cell activation and differentiation, and 3) the resolution of inflammation and
the promotion of healing through induction of matrix synthesis, fibroblast proliferation,
angiogenesis and the clearance of cellular debris. In order to perform these disparate tasks,
macrophages must be capable of inducing the expression of specific subsets of genes in a
coordinated fashion in response to environmental stimuli. The basal activity of tissue resident
macrophages, as well as their ability to respond to environmental stimuli, varies considerably.
This response must be tightly controlled in order to stimulate immunity to infection, while at the
same time, protecting host tissues from inflammatory damage and promoting normal tissue
homeostasis. Here, we propose that receptor tyrosine kinases (RTKs) play a role in fine-tuning
this system.
Expression of at least three distinct families of RTKs has been reported in the
monocyte/macrophage lineage. The receptor for macrophage colony-stimulating factor (c-fms,
CSF-1R) is widely expressed in the monocyte/macrophage lineage[3], and is required for the
development of a number of tissue-resident macrophage populations[4].
This receptor is a
member of the PDGFR superfamily of RTKs , containing five immunoglobulin-like domains in
the extracellular portion of the receptor and a split kinase domain (figure 1a). In contrast, the
Axl/Tyro3/Mer family of receptors[5, 6] contains two immunoglobulin-like domains and two
fibronectin type III repeats in the ectodomain and a contiguous kinase domain with two tandem
tyrosines in the activation loop. The murine STK/human RON receptor[7, 8], a member of the
Figure 1. Receptor Tyrosine Kinases Expressed in the Monocyte/Macrophage
Lineage. A) Cartoon of the conserved structural features of the RON/STK,
Axl/Tyro3/Mer and c-fms receptors and their family members. Green and light blue bars
represent the kinase domain and fibronectin-like repeats, respectively. Half circles
represent Ig domains B) Expression of the murine STK receptor in various cells of the
monocyte/macrophage lineage.
MET family of RTKs, is closely related to the Tyro3 family and shares a similar kinase structure.
The ectodomain of STK, however, is composed of a disulfide linked extracellular α chain and
transmembrane β chain the structure of which are poorly characterized. Recent studies utilizing
the MET receptor suggest that the c-terminal half of the extracellular domain contains four
atypical Ig domains and the N-terminal ligand-binding region adopts a beta-propeller fold similar
to that displayed by the alpha V integrin[9].
While M-CSF has been implicated in the
proliferation, but not the activity, of terminally differentiated macrophages[10], the Tyro3 family
of receptors and STK appear to play a role in regulating the activation of these cells in response to
environmental stimuli[11, 12].
Consistent with the activation of nearly all RTKs, the ligands for the Tyro3 family of
RTKs (Gas6 and Protein S[13-15]) and STK (MSP, macrophage stimulating protein) [16], bind to
the extracellular domain of their respective receptors resulting in the upregulation of kinase
activity. However, RTKs also appear to participate in the recognition of a wide range of both
exogenous and endogenous ligands. Listeria monocytogenes has been shown to gain entry into
hepatocytes through the interaction of InlB with the Met receptor[17].
In addition, Tyro3
receptors play a direct role in the recognition of apoptotic cells through the interaction of Gas6
with phosphatidyl serine on the surface of apoptotic cells, and macrophages from Mer KO mice
are defective in the clearance of apoptotic thymocytes[18]. Alternatively, these RTKs can also
regulate the expression or activity of classic PRRs. For example, signaling through the STK
receptor regulates the activation of the αMβ2 integrin, CR3, which recognizes a variety of
exogenous and endogenous ligands including C3bi, ICAM-1, LPS and zymosan. CR3 activation
by the MSP/STK signaling pathway results in the phagocytosis of C3bi-coated erythrocytes and
enhanced macrophage binding to ICAM-1, via a PI3-kinase/PKCζ-dependent mechanism[19]. In
addition, MSP stimulation of primary peritoneal macrophages induces the expression of
scavenger receptor A[20], which recognizes the exogenous ligands Lipid A and LTA, as well as
oxLDL and apoptotic cells, resulting in enhanced uptake of acetylated LDL by these cells.
While the Tyro3 family of receptors is reported to be widely expressed by monocytes and
their derivatives, expression of the STK receptor by monocyte/macrophage populations is highly
regulated.
STK/RON is not expressed on circulating monocytes, bone marrow-derived
macrophages, splenic red pulp macrophages or alveolar macrophages, but is expressed on a
number of specialized tissue macrophage populations (figure 1b), including peritoneal
macrophages, osteoclasts, mesangial cells, Kupffer cells, dermal macrophages and marginal zone
macrophages in the spleen [21-23](and unpublished observations). Futhermore, LPS stimulation
of macrophages in vitro or in vivo inhibits expression of STK[24], however the upregulation of
STK expression on day 3 ConA elicited peritoneal macrophages and at sites of wounding has
been demonstrated[21, 23]. Our unpublished data indicate that IL-4, glucocorticoids and hypoxia
(1% oxygen) induce the expression of STK on primary peritoneal macrophages, but not bone
marrow-derived macrophages in vitro, suggesting that these factors may play a role in the
induction of STK on elicited macrophages in vivo in the context of the peritoneal cavity or at sites
of wounding. Based on the restricted expression of STK in cells of the monocyte/macrophage
lineage, we speculate that the MSP/STK signaling pathway may play a role in regulating the
recognition of exogenous and endogenous ligands by tissue resident macrophages as well as
regulating the response of varying macrophage populations to these and other environmental
stimuli.
Kupffer cells account for 80-90% of total fixed tissue macrophages in the body. These
cells reside primarily in the lumen of hepatic sinusoids attached to endothelial cells where they
clear bacteria and endotoxin from the blood transported from the gastrointestinal tract via the
portal vein. Effective clearance of Listeria monocytogenes is dependent on Kupffer cells as
evidenced by increased Listeria in the blood of Kupffer cell-depleted mice. Futhermore, this
clearance is dependent on the interaction between Kupffer cells and neutrophils in an ICAM1/CR3 dependent manner[25]. Mice with a targeted deletion in the gene encoding STK are more
susceptible to infection with Listeria monocytogenes, harboring increased bacterial counts in the
liver, but not the spleen[26]. As an intracellular pathogen, Listeria avoids detection by the innate
immune system by residing in hepatocytes.
Therefore, the initial rapid clearance of these
invaders by macrophages is essential in preventing infection. STK may enhance initial clearance
of Listeria by Kupffer cells through promoting the uptake of complement-opsonized bacterial
products as well as augmenting CR3/ICAM-1-dependent interactions with neutrophils.
Alternatively, STK may enhance clearance of Listeria through the activation of other PRRs, such
as SR-A, which has been shown to be critical in the innate response to infection with Listeria[27].
Subsequently, Kupffer cells lacking STK may be unable to efficiently control the initial infection,
thus allowing for the dissemination of Listeria into the liver.
While MSP, the ligand for STK, was originally isolated from serum due to its ability to
induce chemotaxis and complement-mediated phagocytosis by primary peritoneal macrophages,
studies in recent years have highlighted a pivotal role for the MSP/STK signaling pathway in
regulating the effector functions of macrophages.
MSP stimulation of primary peritoneal
macrophages inhibits the production of nitric oxide (NO)[28, 29] and prostaglandin E2
(PGE2)[30] in response to pro-inflammatory cytokines and LPS, due to an inhibition of the
expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2), respectively.
This inhibition is associated with a decrease in the activation of NFκB in response to LPS in the
presence of MSP/STK[29, 30]. STK-deficient mice exhibit increased susceptibility to LPSinduced septic shock[31-33] and enhanced inflammation in response to nickel-induced lung
injury, associated with increased serum nitrite levels and pulmonary tyrosine nitrosylation[34].
MSP is a serum protein that is produced primarily in the liver and circulates in the serum in an
inactive form. The active form of MSP is generated by proteolytic cleavage by members of the
coagulation cascade[35], and is found in the serum of patients with septic shock. However, mice
with a targeted deletion in MSP do not exhibit enhanced susceptibility to endotoxic shock[36],
suggesting the presence of alternative ligands or ligand-independent activation of STK in vivo. A
deletion in the tyrosine kinase domain of the closely related Mer RTK also results in enhanced
sensitivity to endotoxic shock, and macrophages from these animals produce elevated levels of
TNFα and display increased activation of NFκB in response to stimulation with LPS[37]. Taken
together, these data suggest that RTK expression on tissue-resident and exudate macrophages
limits the activation of NFkB and the production of inflammatory mediators, including NO, by
these cells in response to environmental stimuli, thus protecting host tissues from inflammatory
damage.
In addition to its regulation at the level of iNOS transcription, NO production by
activated macrophages is also regulated through substrate availability. L-arginine is a substrate
for both iNOS and arginase, which drives the production of ornithine, a precursor for polyamine
and proline synthesis. While the effects of NO are primarily cytotoxic, production of ornithine by
macrophages promotes cell proliferation and matrix synthesis. IL-4, a potent inhibitor of NO
production, accomplishes this task by upregulating arginase expression through the activation of
Stat6 and limiting the amount of L-arginine available to iNOS[38]. We have shown that MSP
induces expression of arginase I in primary peritoneal macrophages[20], and cooperates with IL-4
to enhance arginase activity in a Stat6-dependent manner (Wilson and Correll, submitted).
However, unlike IL-4, MSP inhibition of NO is independent of L-arginine availability, suggesting
that the MSP/STK signaling pathway independently regulates both iNOS and arginase
expression. MSP-induced arginase I expression is dependent on the PI3-kinase and p38 MAPK
signaling pathways (Morrison and Correll, unpublished).
Interestingly, resident peritoneal
macrophages, but not bone marrow-derived macrophages, harvested from mice with a targeted
mutation in the lipid phosphatase, SHIP-1, express elevated levels of arginase[39]. The ability of
STK and PI3K to induce arginase I expression in resident macrophages suggests a potential dual
role for RTK signaling in limiting tissue-destructive inflammation and promoting the wound
healing process by tipping the balance of arginine metabolism in macrophages (figure 2).
In addition to the regulation of macrophage effector functions, there is an emerging role
for RTK signaling in regulating the immunomodulatory functions of macrophages.
While
simultaneous stimulation of macrophages with MSP and IFN-γ with or without LPS has little
effect on cytokine production by macrophages, pretreatment of primary peritoneal macrophages
with MSP for 2-4 hours results in the complete inhibition of IL-12 production in response to IFNγ and LPS, due to the inhibition of IL-12 p40 expression[40]. This inhibition appears to result
from a block in Stat-1 tyrosine phosphorylation and ICSBP upregulation induced by IFN-γ. IL12 is a key regulator of IFN-γ production by NK and γδT cells in the early stages of an innate
immune response, and serves to bridge innate and adaptive immunity by promoting the survival
of Th1 cells (reviewed in [41]). Pretreatment of macrophages with MSP also results in the
inhibition of MHC Class II expression in response to both IFN-γ and IL-4, and reduced Th1/Th2
differentiation under polarizing conditions in vitro (Wilson and Correll, submitted). In vivo,
STK-deficient mice exhibit increased inflammation in a Th1-mediated delayed-type
hypersensitivity (DTH) response[31, 33]. Furthermore, macrophages and dendritic cells from
triple-mutant mice for the RTKs Tyro3, Axl and Mer express elevated levels of MHC Class II
and the co-stimulatory molecule, B7-2, in response to LPS and produce increased levels of IL12[42].
These data suggest that, in addition to regulating innate immune responses, the
expression of RTKs on antigen presenting cells may play a key role in modulating T helper cell
differentiation and thus regulating acquired immunity (figure 3, adapted from [1]).
Figure 2. Activation of STK by MSP tips the balance of arginine metabolism
toward ornithine. While pro-inflammatory cytokines and LPS induce expression of
iNOS resulting in the metabolism of arginine to nitric oxide, Th2 cytokines induce
expression of arginase resulting in the production of ornithine. MSP stimulation of the
STK receptor inhibits iNOS expression in response to IFN-γ and LPS and induces the
expression of arginase, thus favoring the metabolism of arginine to ornithine.
Figure 3. MSP/STK limits IFN-γ-induced IL-12 production, MHC Class II
expression and Th1 cell differentiation. IL-12 production by macrophages induces
IFN-γ production by NK and γδ T cells and supports Th1 cell differentiation. IFN-γ also
increases surface expression of MHC Class II on macrophages, resulting in enhanced
antigen presentation. MSP/STK inhibits both IL-12 production and MHC Class II
expression, and stimulation of primary peritoneal macrophages with MSP limits the
ability of these cells to support Th1 differentiation.
While signaling through RTKs has traditionally been shown to promote cell growth and
survival, thus playing a critical role in differentiation and tumorigenesis, the studies described
here have provided the first link between RTK signaling and immune regulation. However, the
mechanism by which these RTKs inhibit macrophage activation remains unclear. IL-10, a potent
inhibitor of classical activation, induces Stat3 phosphorylation, and mice with a tissue-specific
deletion of Stat3 in macrophages develop an intestinal inflammation similar to that observed in
the IL-10 knockout animals and are more susceptible to septic shock[43].
Furthermore,
microarray studies using macrophages from these mice have indicated that IL-10 exerts most, if
not all, of its effects on macrophages through the activation of Stat3[44]. Activation of Stat3 by a
number of wild-type and mutant RTKs, including those of the MET and Tyro3 families, has also
been demonstrated[45-49]. While the effects of the MSP/STK signaling pathway on macrophage
activation are similar to those observed for IL-10, we have demonstrated that STK does not
enhance IL-10 production by peritoneal macrophages either alone or in combination with LPS.
Futhermore, using peritoneal macrophages from IL-10 knockout mice, we have shown that the
induction of arginase[20] and the inhibition of IL-12[40] by MSP are independent of IL-10.
Alternatively, these signaling pathways may provide parallel but distinct functions in regulating
macrophage activation during an immune response. For example, the expression of RTKs on
macrophages could set a threshold which pro-inflammatory stimuli must overcome in order to
induce classical macrophage activation, whereas the induction of IL-10 in response to LPS may
provide an important negative feedback mechanism for limiting the extent and/or duration of this
response.
RTK signaling could ultimately inhibit LPS-induced NFκB activation and IFN-γ-induced
Stat1 tyrosine phosphorylation through the induction of classical negative feedback pathways
(figure 4). Suppressor of cytokine signaling (SOCS) proteins constitute a family of molecules
that provide a negative feedback loop in the regulation of Jak/Stat signaling. IL-10 induces the
Figure 4. Potential mechanisms by which RTKs could limit the activation of
macrophages by IFN-γ and LPS. In other systems, RTKs have been shown to induce
the tyrosine phosphorylation of Stat3, a critical negative regulator of macrophage
activation, and induce expression of SOCS1 and SOCS3. Futhermore, RTKs have been
shown to induce NFκB activation through a PI3K-dependent mechanism and to
upregulate the expression of twist genes. Activation of these signaling pathways could
induce negative-feedback inhibition of IFN-γ and LPS signaling.
expression of SOCS1 and SOCS3 in a Stat3-dependent manner[50, 51] and studies of SOCS1 -/mice have demonstrated that SOCS1 is a critical regulator of both IFN-γ and LPS signaling in
vivo[52, 53], while SOCS3 appears to prevent IFN-γ-like responses in cells stimulated with IL6[54, 55]. Several RTKs have also been shown to induce the expression of SOCS proteins,
suggesting the possibility that RTK signaling could regulate macrophage activation through the
induction of SOCS1 and SOCS3. RTK signaling, has been shown to activate NFκB signaling in
several cell types through the PI3-kinase-, Akt-dependent phosphorylation of IKK[56, 57].
Conversely, PI3-kinase has been shown to be a negative regulator of iNOS expression in
macrophages through sustained activation of NFκB[58], and the inhibition of iNOS by MSP has
been shown to be PI3-kinase-dependent[59]. Furthermore, recent studies have demonstrated that
PI3-kinase negatively regulates the production of IL-12 by dendritic cells and Th1 responses in
vivo[60], and it has been suggested that PI3-kinase functions at the early phase of TLR signaling
to modulate the magnitude of classical macrophage activation[61]. Negative feedback inhibition
of the NFκB signaling pathway has also been demonstrated through the upregulation of IκB and,
more recently, the p65-dependent expression of twist proteins. Twist 1 and Twist 2 are basic
helix-loop-helix transcription factors that are upregulated in response to NFκB and studies from
twist mutant mice demonstrate a role for twist 1 and 2 in the inhibition of p65 transactivation and
the regulation of proinflammatory cytokine production in vivo[62]. Interestingly, the Met RTK
has been shown to induce muscle differentiation through the upregulation of twist1
expression[63], and FGF2 induces expression of twist1 in osteoblasts[64].
The signals that regulate macrophage activation and function must be tightly controlled in
order to promote immunity to infection, while protecting host tissues from inflammatory damage.
While these cells play a critical role in the host response to infection, macrophages are the
primary effector cells in the tissue destruction phase of autoimmunity.
Cytotoxic effector
molecules, such as NO, produced by activated macrophages have been implicated in the
pathogenesis of organ-specific autoimmunity. In addition, IL-12 has been shown to play an
important role in sustaining autoimmunity in several mouse models, through its ability to mediate
the production of IFN-γ and favor a Th1 response. Changes in the threshold of macrophage
activation or reduced ability to clear apoptotic cells can predispose mice to autoimmunity. The
STK and Mer family of RTKs represent a new class of signaling molecules involved in the
regulation of macrophages.
The expression of these RTKs on distinct populations of
macrophages appears to play a role in innate recognition and regulate the threshold for classical
macrophage activation.
In the absence of the Mer receptor, mice develop lupus-like
autoimmunity[65], due at least in part to the inability of MER-deficient macrophages to
efficiently clear apoptotic cells, while triple mutant Mer/Axl/Tyro3 mice develop a severe
lymphoproliferative disorder accompanied by autoimmunity[42]. While STK-deficient mice do
not develop obvious signs of autoimmunity, the absence of STK on an MRL/Lpr background
appears to exacerbate the pathogenesis of disease in these mice (Ray and Correll, unpublished
observations). Due to the ability of RTKs to regulate innate immune recognition, production of
cytotoxic effector molecules and T helper cell activation by macrophages, these receptors may
provide a novel target for the treatment of a wide range of autoimmune disorders.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Gordon, S. (2002) Alternative activation of macrophages. Nat Rev Immunol 3, 2335.
Mosser, D. (2003) The many faces of macrophage activation. J Leuk Biol 73, 209212.
Byrne, P., Guilbert, L., Stanley, E. (1981) Distribution of cells bearing receptors
for a colony-stimulating factor (CSF-1) in murine tissues. J Cell Biol 91, 848-853.
Dai, X.-M., Ryan, G., Hapel, A., Dominguez, M., Russell, R., Kapp, S., Sylvestre,
V., Stanley, E. (2002) Targeted disruption of the mouse colony-stimulating factor
1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency,
increased primitive progenitor cell frequencies, and reproductive defects. Blood
99, 111-120.
Graham, D., Dawson, T., Mullaney, D., Snodgrass, H., Earp, H. (1994) Cloning
and mRNA expression analysis of a novel human protooncogene, c-mer. Cell
Growth Differ 5, 647-657.
Graham, D., Bowman, G., Dawson, T., Stanford, W., Earp, H., Snodgrass, H.
(1995) Cloning and developmental expression analysis of the murine c-mer
tyrosine kinase. Oncogene 10, 2349-2359.
Iwama, A., Okano, K., Sudo, T., Matsuda, U., Suda, T. (1994) Molecular cloning
of a novel receptor tyrosine kinase, STK, derived from enriched hematopoietic
stem cells. Blood 83, 3160-3169.
Ronsin, C., Muscatelli, F., Mattei, M., Breathnach, R. (1993) A novel putative
receptor protein tyrosine kinase of the met family. Oncogene 8, 1195-1202.
Gherardi, E., Youles, M., Miguel, R., Blundell, T., Iamele, L., Gough, J.,
Bandyopadhyay, A., Hartmann, G., Butler, P. (2003) Functional map and domain
structure of MET, the product of the c-met protooncogene and receptor for
hepatocyte growth factor/scatter factor. Proc Natl Acad Sci USA Epub ahead of
print.
Gordon, S., Clarke, S., Greaves, D., Doyle, A. (1995) Molecular immunobiology
of macrophages: recent progress. Curr Opin Immunol 7, 24-33.
Lemke, G., Lu, Q. (20003) Macrophage regulation by Tyro 3 family receptors.
Curr Opin Immunol 15, 31-36.
Wang, M., Zhou, Y., Chen, Y. (2002) Macrophage-stimulating protein and RON
receptor tyrosine kinase: Potential regulators of macrophage inflammatory
activities. Scand J Immunol 56, 545-553.
Sitt, T., Conn, G., Gore, M., Lai, C., Bruno, J., Radziejewski, C., Mattsson, K.,
Fisher, J., Gies, D., Jones, P. (1995) The anticoagulation factor protein S and its
relative, Gas6, are ligands for the Tyro3/Axl family of receptor tyrosine kinases.
Cell 80, 661-70.
Varnum, B., Young, C., Elliott, G., Garcia, A., Bartley, T., Fridell, Y., Hunt, R.,
Trail, G., Clogston, C., Toso, R. (1995) Axl receptor tyrosine kinase stimulated by
the vitamin K-dependent protein encoded by growth-arrest-specific gene 6.
Nature 373, 623-626.
Nagata, K., Ohashi, K., Nakano, T., Arita, H., Zong, C., Hanafusa, H., Mizuno, K.
(1996) Identification of the product of growth arrest-specific gene 6 as a common
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
liand for Axl, Sky and Mer receptor tyrosine kinases. J Biol Chem 271, 3002230027.
Wang, M., Ronsin, C., Gesnel, M., Coupey, L., Skeel, A., Leonard, E.,
Breathnach, R. (1994) Identification of the ron gene product as the receptor for
the human macrophage stimulating protein. Science 266, 117-119.
Shen, Y., Naujokas, M., Park, M., Ireton, K. (2000) InlB-dependent
internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell
103, 501-510.
Scott, R., McMahon, E., Pop, S., Reap, E., Caricchio, R., Cohen, P., Earp, H.,
Matsushima, G. (2001) Phagocytosis and clearance of apoptotic cells is mediated
by MER. Nature 411, 207-211.
Lutz, M., Correll, P. (2003) Activation of CR3-mediated phagocytosis by MSP
requires the RON receptor, tyrosine kinase activity, phosphatidylinositol 3-kinase,
and protein kinase C-zeta. J Leuk Biol 73, 802-814.
Morrison, A., Correll, P. (2002) Activation of the stem cell-derived tyrosine
kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in
the induction of arginase activity in murine peritoneal macrophages. J Immunol
168, 853-860.
Iwama, A., Wang, M., Yamaguchi, N., Ohno, N., Okano, K., Sudo, T., Takeya,
M., Gervais, F., Morissette, C., Leonard, E., Suda, T. (1995) Terminal
differentiation of murine resident peritoneal macrophages is characterized by
expression of the STK protein tyrosine kinase, a receptor for macrophage
stimulating protein. Blood 86, 3394-3403.
Kurihara, N., Iwama, A., Tatsumi, J., Ikeda, K., Suda, T. (1996) Macrophage
stimulating protein activates STK receptor tyrosine kinase on osteoclasts and
facilitates bone resorption by osteoclast-like cells. Blood 87, 3704-3410.
Nanney, L., Skeel, A., Luan, J., Polis, S., Richmond, A., Wang, M., Leonard, E.
(1998) Proteolytic cleavage and activation of pro-macrophage stimulating protein
and upregulation of its receptor in tissue injury. J Invest Dermatol 111, 573-581.
Wang, M., Fung, H., Chen, Y. (2000) Regulation of the RON receptor tyrosine
kinase expression in macrophages: blocking the RON gene transcription by
endotoxin-induced nitric oxide. J Immunol 164, 3815-3821.
Gregory, S., Cousens, L., vanRooijen, N., Dopp, E., Carlos, T., Wing, E. (2002)
Complementary adhesion molecules promote neutrophil-Kupffer cell interaction
and the elimination of bacteria taken up by the liver. J Immunol 168, 308-315.
Lutz, M., F, G., Bernstein, A., Hattel, A., PH, C. (2002) STK receptor tyrosine
kinase regulates susceptibility to infection with Listeria monocytogenes. Infect
Immun 70, 416-418.
Ishiguro, T., Naito, M., Yamamoto, T., Hasegawa, G., Gejyo, F., Mitsuyama, M.,
Suzuki, H., Kodama, T. (2001) Role of macrophage scavenger receptors in
response to Listeria monocytogenes infection in mice. Am J Pathol 158, 179-188.
Wang, M., Cox, G., Yoshimura, T., Sheffler, L., Skeel, A., Leonard, E. (1994)
Macrophage stimulating protein inhibits induction of nitric oxide production by
endotoxin or cytokine stimulated mouse macrophages. J Biol Chem 269, 1402714031.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
Liu, Q., Fruit, K., Ward, J., Correll, P. (1999) Negative regulation of macrophage
activation in response to IFN-gamma and lipopolysaccharide by the STK/RON
receptor tyrosine kinase. J Immunol 163, 6606-6613.
Zhou, Y., Chen, Y., Fisher, J., Wang, M. (2002) Activation of the RON receptor
tyrosine kinase by macrophage stimulating protein inhibits inducible
cyclooxygenase-2 expression in murine macrophages. J Biol Chem 277, 3810438110.
Correll, P., Iwama, A., Tondat, S., Mayrhofer, G., Suda, T., A, B. (1997)
Deregulated inflammatory response in mice lacking the STK/RON receptor
tyrosine kinase. Genes Funct 1, 69-83.
Muraoka, R., Sun, W., Cobert, M., Waltz, S., Witte, D., Degan, J., Degan, S.
(1999) The RON/STK receptor tyrosine kinase is essential for peri-implantation
development in the mouse. J Clin Invest 103, 1277.
Waltz, S., Eaton, L., K, T.-E., Hess, K., Peace, B., Ihlendorf, J., Wang, M.,
Kaestner, K., Degen, S. (2001) Ron-mediated cytoplasmic signaling is
dispensable for viability but is required to limit inflammatory responses. J Clin
Invest 108, 567-576.
McDowell, S., Mallakin, A., Bachurski, C., K, T.-E., Prows, D., Bruno, T.,
Kaestner, K., Witte, D., Melin-Aldana, H., Degen, S., Leikauf, G., Waltz, S.
(2002) The role of the receptor tyrosine kinase Ron in nickel-induced acute lung
injury. Am J Respir Cell Mol Biol 26, 99-104.
Wang, M., Yoshimura, T., Skeel, A., Leonard, E. (1994) Proteolytic conversion of
single chain precursor macrophage stimulating protein to a biologically active
heterodimer by contact enzymes of the coagulation cascade. J Biol Chem 269,
3436-3440.
Bezerra, J., Carrick, T., Degen, J., Witte, D., Degen, S. (1998) Biological effects
of targeted inactivation of hepatocyte growth factor-like protein in mice. J Clin
Invest 101, 1175-1183.
Camenisch, T., Koller, B., Earp, H., Matsushima, G. (1999) A novel receptor
tyrosine kinase, Mer, inhibits TNFα production and lipopolysaccharide-induced
endotoxic shock. J Immunol 162, 3498-3503.
Rutschman, R., Lang, R., Hesse, M., Ihle, J., Wynn, T., Murray, P. (2001) Cutting
edge: Stat6-dependent substrate depletion regulates nitric oxide production. J
Immunol 166, 2173-2177.
Rauh, M., Kalesnikoff, J., Hughes, M., Sly, L., Lam, V., Krystal, G. (2003) Role
of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and
macrophages. Biochem Soc Trans 31, 286-91.
Morrison, A., Wilson, C., Ray, M., Correll, P. Macrophage stimulating protein
(MSP), the ligand for the STK/RON receptor tyrosine kinase, inhibits IL-12
production by primary peritoneal macrophages stimulated with IFN-gamma and
LPS. J Immunol in press.
Trinchieri, G. (2003) Interleukin-12 and the regulation of innate resistance and
adaptive immunity. Nat Rev Immunol 3, 133-146.
Lu, Q., Lemke, G. (2001) Homeostatic regulation of the immune system by
receptor tyrosine kinases of the Tyro3 family. Science 293, 306-311.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
Takeda, K., Clausen, B., Kaisho, T., Tsujimura, T., Terada, N., Forster, I., Akira,
S. (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice
devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39.
Lang, R., Patel, D., Morris, J., Rutschman, R., Murray, P. (2002) Shaping gene
expression in activated and resting primary macrophages by IL-10. J Immunol
169, 2253-2263.
Song, L., Turkson, J., Karras, J., Jove, R., Haura, E. (2003) Activation of Stat3 by
receptor tyrosine kinases and cytokines regulates survival in human non-small cell
carcinoma cells. Oncogene 22, 4150-4165.
Zhang, Y., Wang, L., Jove, R., Vande Woude, G. (2002) Requirement of Stat3
signaling for HGF/SF-Met mediated tumorigenesis. Oncogene 21, 217-226.
Boccaccio, C., Ando, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C.,
Comoglio, P. (1998) Induction of epithelial tubules by growth factor HGF
depends onthe STAT pathway. Nature 391, 285-288.
Besser, D., Bromberg, J., Darnell, J., Hanafusa, H. (1999) A single amino acid
substitution in the v-Eyk intracellular domain results in activation of Stat3 and
enhances cellular transformation. Mol Cell Biol 19, 1401-1409.
Yanagita, M., Arai, H., Nakano, T., Ohashi, K., Mizuno, K., Fukatsu, A., Doi, T.,
Kita, T. (2001) Gas6 induces mesangial cell proliferation via latent transcription
factor STAT3. J Biol Chem 276, 42364-42369.
Ding, Y., Chen, D., Tarcsafalvi, A., Su, R., Qin, L., Bromberg, J. (2003)
Suppressor of cytokine signaling 1 inhibits IL-10-mediated immune responses. J
Immunol 170, 1383-1391.
Ito, S., Ansari, P., Sakatsume, M., Dickensheets, H., Vazquez, N., Donnelly, R.,
Larner, A., Finbloom, D. (1999) Interleukin-10 inhibits expression of both
interferon α− and interferon γ- induced genes by suppressing tyrosine
phosphorylation of STAT1. Blood 93, 1456-1463.
Kinjyo, I., Hanada, T., Inagaki-Ohara, K., Mori, H., Aki, D., Ohishi, M., Yoshida,
H., Kubo, M., Yoshimura, A. (2002) SOCS1/JAB is a negative regulator of LPSinduced macrophage activation. Immunity 17, 583-591.
Nakagawa, R., Naka, T., Tsutsui, H., Fujimoto, M., Kimura, A., Abe, T., Seki, E.,
Sato, S., Takeuchi, O., Takeda, K., Akira, S., Yamanishi, K., Kawase, I.,
Nakanishi, K., Kishimoto, T. (2002) SOCS-1 participates in negative regulation
of LPS responses. Immunity 17, 677-687.
Lang, R., Pauleau, A.-L., Parganas, E., Takahashi, Y., Mages, J., Ihle, J.,
Rutschman, R., Murray, P. (2003) SOCS3 regulates the plasticity of gp130
signaling. Nat Immunol 4, 546-550.
Croker, B., Krebs, D., Zhang, J.-G., Womald, S., Willson, T., Stanley, E., Robb,
L., Greenhalgh, C., Forster, I., Clausen, B., Nicola, N., Metcalf, D., Hilton, D.,
Roberts, A., Alexander, W. (2003) SOCS3 negatively regulates IL-6 signaling in
vivo. Nat Immunol 4, 540-545.
Madrid, L., Wang, C., Guttridge, D., Schottelius, A., Baldwin, A., Mayo, M.
(2000) Akt suppresses apoptosis b stimulating the transactivation potential of the
RelA/p65 subunit of NF-kappaB. Mol Cell Biol 20, 1626-1638.
Romashkova, J., Makarov, S. (1999) NF-kappaB is a target of AKT in antiapoptotic PDGF signalling. Nature 401, 86-90.
58.
59.
60.
61.
62.
63.
64.
65.
Diaz-Guerra, M., Castrilo, A., Martin-Sanz, P., Bosca, L. (1999) Negative
regulation by phosphatidylinositol 3-kinase of inducible nitric oxide synthase
expression in macrophages. J Immunol 162, 6184-6190.
Chen, Y., Fisher, J., Wang, M. (1998) Activation of the RON receptor tyrosine
kinase inhibits inducible nitric oxide synthase (iNOS) expression by murine
peritoneal macrophages: phosphatidylinositol-3 kinase is required for RONmediated inhibition of iNOS expression. J Immunol 161, 4950-4959.
Fukao, T., Tanabe, M., Terauchi, Y., Ota, Y., Matsuda, S., Asano, T., Kadowaki,
T., Takeuchi, T., Koyasu, S. (2002) PI3K-mediated negative feedback regulation
of IL-12 production in DCs. Nat Immunol 3, 875-881.
Fukao, T., Koyasu, S. (2003) PI3K and negative regulation of TLR signaling.
Trends Immunol 24, 358.
Sosic, D., Richardson, J., Yu, K., Ornitz, D., Olson, E. (2003) Twist regulates
cytokine gene expression through a negative feedback loop that represses NFkappaB activity. Cell 112, 169-180.
Leshem, Y., Spicer, D., Gal-Levi, R., Halevy, O. (2000) Hepatocyte growth factor
(HGF) inhibits skeletal muscle cell differentiation: a role for the bHLH protein
twist and the cdk inhibitor p27. J Cell Physiol 184, 101-109.
Fang, M., Glackin, C., Sadhu, A., McDougall, S. (2001) Transcriptional
regulation of alpha 2(I) collagen gene expression by fibroblast growth factor-2 in
MC3T3-E1 osteoblast-like cells. J Cell Biochem 80, 550-559.
Cohen, P., Caricchio, R., Abraham, V., Camenisch, T., Jennette, J., Roubey, R.,
Earp, H., Matsushima, G., Reap, E. (2002) Delayed apoptotic cell clearance and
lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J
Exp Med 196, 135-140.