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1.  Negative Regulation of Osteoclast Precursor Differentiation by CD11b and β2 Integrin-BCL6 Signaling 
Negative regulation of osteoclastogenesis is important for bone homeostasis and prevention of excessive bone resorption in inflammatory and other diseases. Mechanisms that directly suppress osteoclastogenesis are not well understood. In this study we investigated regulation of osteoclast differentiation by the β2 integrin CD11b/CD18 that is expressed on myeloid lineage osteoclast precursors. CD11b-deficient mice exhibited decreased bone mass that was associated with increased osteoclast numbers and decreased bone formation. Accordingly, CD11b and β2 integrin signaling suppressed osteoclast differentiation by preventing RANKL-induced induction of the master regulator of osteoclastogenesis NFATc1 and of downstream osteoclast-related NFATc1 target genes. CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation of RANK expression and induction of recruitment of the transcriptional repressor BCL6 to the NFATC1 gene. These findings identify CD11b as a negative regulator of the earliest stages of osteoclast differentiation, and provide an inducible mechanism by which environmental cues suppress osteoclastogenesis by activating a transcriptional repressor that makes genes refractory to osteoclastogenic signaling.
PMCID: PMC3522783  PMID: 22893614
osteoclast; signaling; integrin; CD11b; BCL6
2.  Regulation of Inflammatory Responses in Tumor Necrosis Factor - Activated and Rheumatoid Arthritis Synovial Macrophages by Janus Kinase Inhibitors 
Arthritis and rheumatism  2012;64(12):3856-3866.
Inhibitors of the Janus kinases (JAKs) have been developed as anti-inflammatory and immunosuppressive agents and are currently undergoing testing in clinical trials. The JAK inhibitors CP-690,550 (tofacitinib) and INCB018424 (ruxolitinib) have demonstrated clinical efficacy in rheumatoid arthritis (RA). However, the mechanisms that mediate the beneficial actions of these compounds are not known. In this study, we examined the effects of both JAK inhibitors on inflammatory and tumor necrosis factor (TNF) responses in human macrophages (MΦs).
In vitro studies were performed with peripheral blood MΦs from healthy donors treated with TNF and synovial fluid MΦs from patients with RA. Levels of activated signal transducer and activator of transcription (STAT) proteins and other transcription factors were detected by Western blot, and gene expression was measured by real-time polymerase chain reaction. In vivo effects of JAK inhibitors were evaluated in the K/BxN serum-transfer model of arthritis.
JAK inhibitors suppressed activation and expression of STAT1 and downstream inflammatory target genes in TNF-stimulated and RA synovial macrophages. In addition, JAK inhibitors decreased nuclear localization of NF-κB subunits in TNF-stimulated and RA synovial macrophages. CP-690,550 significantly decreased IL6 expression in synovial MΦs. JAK inhibitors augmented nuclear levels of NFATc1 and cJun, followed by increased formation of osteoclast-like cells. CP-690,550 strongly suppressed K/BxN arthritis that is dependent on macrophages but not on lymphocytes.
Our findings demonstrate that JAK inhibitors suppress macrophage activation and attenuate TNF responses, and suggest that suppression of cytokine/chemokine production and innate immunity contributes to the therapeutic efficacy of JAK inhibitors.
PMCID: PMC3510320  PMID: 22941906
macrophages; TNF; STAT1; rheumatoid arthritis; JAK inhibitors
3.  ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes1 
Immunoreceptor tyrosine based activation motif (ITAM)-coupled receptors play an essential role in regulating macrophage activation and function by cross-regulating signaling from heterologous receptors. We investigated mechanisms by which ITAM-associated receptors inhibit type I interferon (IFN-α/β) signaling in primary human macrophages and tested the effects of simultaneous ligation of ITAM-associated receptors and TLR4 on TLR4-induced Jak-STAT signaling that is mediated by autocrine IFN-β. Preligation of ITAM-coupled β2 integrins and FcγRs inhibited proximal signaling by the type I IFN receptor IFNAR. Cross-inhibition of IFNAR signaling by β2 integrins resulted in decreased Jak1 activation and was mediated by partial downregulation of the IFNAR1 subunit and MAPK-dependent induction of USP18, which blocks the association of Jak1 with IFNAR2. Simultaneous engagement of ITAM-coupled β2 integrins or Dectin-1 with TLR4 did not affect TLR4-induced direct activation of inflammatory target genes such as TNF or IL6, but abrogated subsequent induction of IFN response genes that is mediated by autocrine IFN-β signaling. Type I IFNs promote macrophage death after infection by Listeria monocytogenes. Consequently, attenuation of IFN responses by β2 integrins protected primary human macrophages from Listeria monocytogenes induced apoptosis. These results provide a mechanism for cross-inhibition of type I IFN signaling by ITAM-coupledβ2 integrins and demonstrate that ITAM signaling qualitatively modulates macrophage responses to PAMPs and pathogens by selectively suppressing IFN responses.
PMCID: PMC3311708  PMID: 22368279
monocytes/macrophages; cytokines; inflammation; TLRs; signal transduction
4.  Feedback inhibition of osteoclastogenesis during inflammation by IL-10, M-CSF receptor shedding, and induction of IRF8 
Inflammation plays a key role in excessive bone loss in conditions such as rheumatoid arthritis and periodontitis. An important paradigm in immunology is that inflammatory factors activate feedback inhibition mechanisms to restrain inflammation and limit associated tissue damage. We hypothesized that inflammatory factors would activate similar feedback mechanisms to restrain bone loss in inflammatory settings. We have identified three mechanisms that inhibit osteoclastogenesis and are induced by inflammatory factors, such as toll-like receptor ligands and cytokines: downregulation of expression of costimulatory molecules such as TREM-2; induction of shedding and thereby inactivation of the M-CSF receptor c-Fms, leading to decreased RANK transcription; and induction of transcriptional repressors such as interferon regulatory factor 8. It is likely that these mechanisms work in a complementary and cooperative manner to fine tune the extent of osteoclastogenesis in inflammatory settings, and their augmentation may represent an alternative therapeutic approach to suppress bone resorption.
PMCID: PMC3263822  PMID: 22082370
inflammation; osteoclasts; toll-like receptors; M-CSF; c-Fms; IRF8
5.  Inflammatory signaling in macrophages: Transitions from acute to tolerant and alternative activation states 
European Journal of Immunology  2011;41(9):2477-2481.
Acute inflammatory activation of macrophages by Toll-like and related receptors is characterized by transient activation of MAPK-, NF-κB- and IRF-mediated signaling pathways and expression of pro-inflammatory genes. This activation state is inherently unstable and often transitions into a state of `tolerance' characterized by diminished signaling, repressive chromatin modifications, and an alternative gene expression program. This Viewpoint describes signaling and epigenetic mechanisms associated with transition to tolerant states, which are proposed to correspond to alternative activation states programmed by the original inflammatory stimuli.
PMCID: PMC3264328  PMID: 21952800
Alternative activation; Epige netics; Macrophages; Signal transduction; Tolerance
6.  TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J 
The Notch-driven transcription factor RBP-J inhibits osteoclast formation in response to TNF.
Tumor necrosis factor (TNF) plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in diseases such as rheumatoid arthritis and periodontitis. Mechanisms that regulate the direct osteoclastogenic properties of TNF to limit pathological bone resorption in inflammatory settings are mostly unknown. Here, we show that the transcription factor recombinant recognition sequence binding protein at the Jκ site (RBP-J) strongly suppresses TNF-induced osteoclastogenesis and inflammatory bone resorption, but has minimal effects on physiological bone remodeling. Myeloid-specific deletion of RBP-J converted TNF into a potent osteoclastogenic factor that could function independently of receptor activator of NF-κB (RANK) signaling. In the absence of RBP-J, TNF effectively induced osteoclastogenesis and bone resorption in RANK-deficient mice. Activation of RBP-J selectively in osteoclast precursors suppressed inflammatory osteoclastogenesis and arthritic bone resorption. Mechanistically, RBP-J suppressed induction of the master regulator of osteoclastogenesis (nuclear factor of activated T cells, cytoplasmic 1) by attenuating c-Fos activation and suppressing induction of B lymphocyte–induced maturation protein-1, thereby preventing the down-regulation of transcriptional repressors such as IRF-8 that block osteoclast differentiation. Thus, RBP-J regulates the balance between activating and repressive signals that regulate osteoclastogenesis. These findings identify RBP-J as a key upstream negative regulator of osteoclastogenesis that restrains excessive bone resorption in inflammatory settings.
PMCID: PMC3280875  PMID: 22249448
7.  TNF Induces Endotoxin Tolerance Mediated by GSK3 in Macrophages 
Nature Immunology  2011;12(7):607-615.
Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production and attendant toxicity, is induced by prior exposure of macrophages to TLR ligands. Induction of tolerance by endogenous cytokines has not been investigated. We show that prior exposure to TNF induces a tolerant state in macrophages, with diminished cytokine production on LPS challenge and protection from LPS-induced lethality. TNF-induced tolerization was mediated by coordinate action of two inhibitory mechanisms, suppression of LPS-induced signaling and chromatin remodeling. Mechanistically, TNF-induced tolerance was distinct from TLR-induced tolerance as it was dependent on GSK3, which suppressed chromatin accessibility and promoted rapid termination of NF-κB signaling by augmenting negative feedback by A20 and I-κBα. These results reveal an unexpected homeostatic function of TNF and provide a GSK3-mediated mechanism for preventing prolonged and excessive inflammation.
PMCID: PMC3258532  PMID: 21602809
8.  Downregulation of Friend Leukemia Virus Integration 1 as a Feedback Mechanism That Restrains Lipopolysaccharide Induction of Matrix Metalloproteases and Interleukin-10 in Human Macrophages 
The E26 transformation-specific (Ets) proteins are a family of transcription factors with important roles in a variety of cellular processes ranging from proliferation and differentiation to transformation and metastasis. Tissue-specific expression of Ets proteins and their ability to interact with other families of transcription factors contribute to their versatility. In this study, we investigated the regulation of Ets factors in primary human monocytes and macrophages, and their role in matrix metalloprotease (MMP) and cytokine production. The macrophage-activating Toll-like receptor ligand, lipopolysaccharide (LPS), induced the expression of Ets family members epithelium-specific Ets factor 3 (ESE-3) and TEL-2 but rapidly suppressed Friend leukemia virus integration 1 (FLI-1) expression. Modulation of FLI-1 expression using either RNA interference or forced expression identified a positive role for FLI-1 in contributing to LPS-induced expression of MMP-1, MMP-3, MMP-10, and interleukin-10 (IL-10). Thus, the rapid downregulation of FLI-1 expression after LPS stimulation attenuates the induction of various MMPs and IL-10 under inflammatory conditions. In contrast, the expression of IL-6 and TNFα and the effects of interferon (IFN)γ on LPS responses were not dependent on FLI-1. Our results define a novel FLI-1-mediated self-regulatory feedback loop that limits MMP expression and thus may attenuate extent of tissue destruction associated with inflammatory responses.
PMCID: PMC3004135  PMID: 20879862
9.  Suppression of TNF-αand IL-1 Signaling Identifies a Mechanism of Homeostatic Regulation of Macrophages by IL-27 
IL-27 is a pleiotropic cytokine with both activating and inhibitory functions on innate and acquired immunity. IL-27 is expressed at sites of inflammation in cytokine-driven autoimmune/inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and sarcoidosis. However, its role in modulating disease pathogenesis is still unknown. In this study, we found that IL-27 production is induced by TNF-α in human macrophages (Mϕ) and investigated the effects of IL-27 on the responses of primary human Mϕ to the endogenous inflammatory cytokines TNF-a and IL-1. In striking contrast to IL-27–mediated augmentation of TLR-induced cytokine production, we found that IL-27 suppressed Mϕ responses to TNF-α and IL-1β, thus identifying an anti-inflammatory function of IL-27. IL-27 blocked the proximal steps of TNF-α signaling by downregulating cell-surface expression of the signaling receptors p55 and p75. The mechanism of inhibition of IL-1 signaling was downregulation of the ligand-binding IL-1RI concomitant with increased expression of the receptor antagonist IL-1Ra and the decoy receptor IL-1RII. These findings provide a mechanism for suppressive effects of IL-27 on innate immune cells and suggest that IL-27 regulates inflammation by limiting activation of Mf by inflammatory cytokines while preserving initial steps in host defense by augmenting responses to microbial products.
PMCID: PMC3019240  PMID: 20971923
10.  Regulation of type I interferon responses 
Nature reviews. Immunology  2014;14(1):36-49.
Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.
PMCID: PMC4084561  PMID: 24362405
11.  Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1 
Several signaling pathways including the Notch pathway can modulate Toll-like receptor (TLR) activation to achieve responses most appropriate for the environment. One mechanism of TLR-Notch crosstalk is TLR-induced expression of Notch ligands Jagged and Delta that feed back to engage Notch receptors on TLR-activated cells. In this study, we investigated mechanisms by which TLRs induce Notch ligand expression in primary macrophages. TLRs induced Jagged1 expression rapidly and independently of new protein synthesis. Jagged1 induction was augmented by interferon (IFN)-γ, was partially dependent on canonical TLR-activated NF-κB and MAPK signaling pathways, and elevated Jagged1 expression augmented TLR-induced IL-6 production. Strikingly, TLR-induced Jagged1 expression was strongly dependent on the Notch master transcriptional regulator RBP-J, and also on upstream components of the Notch pathway γ-secretase and Notch1 and Notch2 receptors. Thus, Jagged1 is an RBP-J target gene that is activated in a binary manner by TLR and Notch pathways. Early and direct cooperation between TLR and Notch pathways leads to Jagged1-RBP-J-mediated autoamplification of Notch signaling that can modulate later phases of the TLR response.
PMCID: PMC3010732  PMID: 20870935
12.  Calcium-Activated Pathways and Oxidative Burst Mediate Zymosan-Induced Signaling and IL-10 Production in Human Macrophages 
Outside of the TLR paradigm, there is little understanding of how pathogen recognition at the cell surface is linked to functional responses in cells of the innate immune system. Recent work in this area demonstrates that the yeast particle zymosan, by binding to the β-glucan receptor Dectin-1, activates an ITAM-Syk–dependent pathway in dendritic cells, which is required for optimal cytokine production and generation of an oxidative burst. It remains unclear how activation of Syk is coupled to effector mechanisms. In human macrophages, zymosan rapidly activated a calcium-dependent pathway downstream of Dectin-1 and Syk that led to activation of calmodulin-dependent kinase II and Pyk2. Calmodulin-dependent kinase and Pyk2 transduced calcium signals into activation of the ERK–MAPK pathway, CREB, and generation of an oxidative burst, leading to downstream production of IL-10. These observations identify a new calcium-mediated signaling pathway activated by zymosan and link this pathway to both inflammatory and anti-inflammatory responses in macrophages.
PMCID: PMC3016855  PMID: 20400701
13.  Indirect Inhibition of Toll-like Receptor and Type I Interferon Responses by ITAM-coupled Receptors and Integrins 
Immunity  2010;32(4):518-530.
An important function of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors is cross-regulation of heterologous receptor signaling, but mechanisms of cross-inhibition are poorly understood. We show that high avidity ligation of ITAM-coupled β2 integrins and FcγRs in macrophages inhibited type I interferon receptor and Toll-like receptor (TLR) signaling and induced expression of interleukin-10 (IL-10), signaling inhibitors SOCS3, ABIN-3 and A20, and repressors of cytokine gene transcription STAT3 and Hes1. Induction of inhibitors was dependent on a pathway comprised of signaling molecules DAP12, Syk, and Pyk2 that coupled to downstream kinases p38 and MSKs, and required integration of IL-10-dependent and independent signals. ITAM-induced inhibitors abrogated TLR responses by cooperatively targeting distinct steps in TLR signaling. Inhibitory signaling was suppressed by IFN-γ and attenuated in inflammatory arthritis synovial macrophages. These results provide an indirect mechanism of cross-inhibition of TLRs and delineate a signaling pathway important for deactivation of macrophages.
PMCID: PMC2862476  PMID: 20362473
14.  Type I Interferon: A New Player in TNF Signaling 
TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we will discuss the role of an IFN-β-mediated autocrine loop in regulation of gene expression program induced by TNF in myeloid cells.
PMCID: PMC2827816  PMID: 20173389
15.  Inhibition of RANK Expression and Osteoclastogenesis by TLRs and IFN-γ in Human Osteoclast Precursors1 
TLRs have been implicated in promoting osteoclast-mediated bone resorption associated with inflammatory conditions. TLRs also activate homeostatic mechanisms that suppress osteoclastogenesis and can limit the extent of pathologic bone erosion associated with infection and inflammation. We investigated mechanisms by which TLRs suppress osteoclastogenesis. In human cell culture models, TLR ligands suppressed osteoclastogenesis by inhibiting expression of receptor activator of NF-κB (RANK), thereby making precursor cells refractory to the effects of RANKL. Similar but less robust inhibition of RANK expression was observed in murine cells. LPS suppressed generation of osteoclast precursors in mice in vivo, and adsorption of LPS onto bone surfaces resulted in diminished bone resorption. Mechanisms that inhibited RANK expression were down-regulation of RANK transcription, and inhibition of M-CSF signaling that is required for RANK expression. TLRs inhibited M-CSF signaling by rapidly down-regulating cell surface expression of the M-CSF receptor c-Fms by a matrix metalloprotease- and MAPK-dependent mechanism. Additionally, TLRs cooperated with IFN-γ to inhibit expression of RANK and of the CSF1R gene that encodes c-Fms, and to synergistically inhibit osteoclastogenesis. Our findings identify a new mechanism of homeostatic regulation of osteoclastogenesis that targets RANK expression and limits bone resorption during infection and inflammation.
PMCID: PMC2783334  PMID: 19890054
16.  IL-10 Suppresses Calcium-mediated Costimulation of RANK Signaling During Human Osteoclast Differentiation by Inhibiting TREM-2 Expression 
Induction of effective osteoclastogenesis by RANK requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of CaMKII and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Downregulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.
PMCID: PMC2742169  PMID: 19625651
17.  Regulation of IFN and TLR Signaling During Macrophage Activation by Opposing Feedforward and Feedback Inhibition Mechanisms 
Immunological reviews  2008;226:41-56.
Activated macrophages and their inflammatory products play a key role in innate immunity and in pathogenesis of autoimmune/inflammatory diseases. Macrophage activation needs to be tightly regulated to rapidly mount responses to infectious challenges but to avoid toxicity associated with excessive activation. Rapid and potent macrophage activation is driven by cytokine-mediated feedforward loops, while excessive activation is prevented by feedback inhibition. Here we discuss feedforward mechanisms that augment macrophage responses to Toll-like receptor (TLR) ligands and cytokines that are mediated by signal transducer and activator of transcription 1 (STAT1) and induced by interferon-γ (IFN-γ). IFN-γ also drives full macrophage activation by inactivating feedback inhibitory mechanisms, such as those mediated by IL-10 and STAT3. Priming of macrophages with IFN-γ reprograms cellular responses to other cytokines, such as type I IFNs and IL-10, with a shift toward pro-inflammatory STAT1-dominated responses. Similar but partially distinct priming effects are induced by other cytokines that activate STAT1, including type I IFNs and interleukin-27. We propose a model whereby opposing feedforward and feedback inhibition loops crossregulate each other to fine tune macrophage activation. In addition, we discuss how dysregulation of the balance between feedforward and feedback inhibitory mechanisms can contribute to the pathogenesis of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus.
PMCID: PMC2630590  PMID: 19161415
monocytes/macrophages; cytokine receptors; Toll-like receptors/pattern-recognition receptors; signal transduction; inflammation
18.  LPS-induced Expression of MMPs in Human Monocytes is Suppressed by IFN-γ via Superinduction of ATF-3 and Suppression of AP-1 Proteins 
Matrix metalloproteinases (MMPs) are induced during inflammatory responses and are important for immune regulation, angiogenesis, wound healing and tissue remodeling. Expression of MMPs needs to be tightly controlled to avoid excessive tissue damage. In this study we investigated the regulation of MMP expression by inflammatory factors in primary human monocytes and macrophages. IFNγ, which augments inflammatory cytokine production in response to macrophage-activating factors such as Toll-like receptor (TLR) ligands, instead broadly suppressed TLR-induced MMP expression. Inhibition of MMP expression was dependent on STAT1 and required de novo protein synthesis. IFNγ strongly enhanced TLR-induced expression of the transcriptional repressor ATF-3 in a STAT1-dependent manner, which correlated with recruitment of ATF-3 to the endogenous MMP-1 promoter as detected by chromatin immunoprecipitation assays. RNA interference experiments further supported a role for ATF-3 in suppression of MMP-1 expression. In addition, IFNγ suppressed DNA binding by AP-1 transcription factors that are known to promote MMP expression and a combination of supershift, RNA interference and overexpression experiments implicated AP-1 family member Fra-1 in the regulation of MMP-1 expression. These results define an IFNγ-mediated homeostatic loop that limits the potential for tissue damage associated with inflammation, and identify transcriptional factors that regulate MMP expression in myeloid cells in inflammatory settings.
PMCID: PMC2610354  PMID: 18802113
LPS; IFNγ; STAT1; ATF-3; Macrophages
Positive regulation of cell migration by chemotactic factors and downstream signaling pathways has been extensively investigated. In contrast, little is known about factors and mechanisms that induce migration arrest, a process important for retention of cells at inflammatory sites and homeostatic regulation of cell trafficking. In this study we found that IFN-γ directly inhibited monocyte migration by suppressing remodeling of the actin cytoskeleton and cell polarization in response to the chemokine CCL2. Inhibition was dependent on STAT1 and downstream genes, whereas STAT3 promoted migration. IFN-γ did not affect proximal CCL2 signaling, but altered monocyte responses to CCL2 by modulating the activity of the GTPases Rac and Cdc42 and the downstream PAK kinase that regulate the cytoskeleton and cell polarization. These results identify a new role for IFN-γ in arresting monocyte chemotaxis by a mechanism that involves modulation of cytoskeleton remodeling. Crosstalk between Jak-STAT and Rac/Cdc42 GTPase-mediated signaling pathways provides a molecular mechanism by which cytokines can regulate cell migration.
PMCID: PMC2742170  PMID: 18523269
IFN-γ; Monocyte; Migration; STAT1; Signal transduction
20.  Synergistic Activation of Inflammatory Cytokine Genes by Interferon-γ-induced Chromatin Remodeling and Toll-like Receptor Signaling 
Immunity  2013;39(3):10.1016/j.immuni.2013.08.009.
Synergistic activation of inflammatory cytokine genes by interferon-γ (IFN-γ) and Toll-like receptor (TLR) signaling is important for innate immunity and inflammatory disease pathogenesis. Enhancement of TLR signaling, a previously proposed mechanism, is insufficient to explain strong synergistic activation of cytokine production in human macrophages. Rather, we found that IFN-γ induced sustained occupancy of transcription factors STAT1, IRF-1 and associated histone acetylation at promoters and enhancers at the TNF, IL6 and IL12B loci. This priming of chromatin did not activate transcription, but greatly increased and prolonged recruitment of TLR4-induced transcription factors and RNA polymerase II to gene promoters and enhancers. Priming sensitized cytokine transcription to suppression by Jak inhibitors. Genome-wide analysis revealed pervasive priming of regulatory elements by IFN-γ, and linked coordinate priming of promoters and enhancers with synergistic induction of transcription. Our results provide a synergy mechanism whereby IFN-γ creates a primed chromatin environment to augment TLR-induced gene transcription.
PMCID: PMC3857147  PMID: 24012417
21.  Twist mediates suppression of inflammation by type I IFNs and Axl 
The Journal of Experimental Medicine  2006;203(8):1891-1901.
Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFα production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFα production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFα production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-κB–dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFα production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.
PMCID: PMC2118370  PMID: 16831897
22.  PTPN22 in autoimmunity: different cell and different way 
Immunity  2013;39(1):91-93.
The tyrosine phosphatase PTPN22 regulates T cell receptor signaling. In this issue of Immunity, Wang et al. (2013) show that in myeloid cells PTPN22 potentiates TLR-induced type I IFN production and that autoimmunity-associated allele PTPN22W encodes a reduced-function variant.
PMCID: PMC3785409  PMID: 23890067
23.  Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis 
The Journal of Experimental Medicine  2003;197(11):1573-1583.
Interleukin-10 (IL-10) is a potent deactivator of myeloid cells that limits the intensity and duration of immune and inflammatory responses. The activity of IL-10 can be suppressed during inflammation, infection, or after allogeneic tissue transplantation. We investigated whether inflammatory factors suppress IL-10 activity at the level of signal transduction. Out of many factors tested, only ligation of Fc receptors by immune complexes inhibited IL-10 activation of the Jak-Stat signaling pathway. IL-10 signaling was suppressed in rheumatoid arthritis joint macrophages that are exposed to immune complexes in vivo. Activation of macrophages with interferon-γ was required for Fc receptor–mediated suppression of IL-10 signaling, which resulted in diminished activation of IL-10–inducible genes and reversal of IL-10–dependent suppression of cytokine production. The mechanism of inhibition involved decreased cell surface IL-10 receptor expression and Jak1 activation and was dependent on protein kinase C delta. These results establish that IL-10 signaling is regulated during inflammation and identify Fc receptors and interferon-γ as important regulators of IL-10 activity. Generation of macrophages refractory to IL-10 can contribute to pathogenesis of inflammatory and infectious diseases characterized by production of interferon-γ and immune complexes.
PMCID: PMC2193912  PMID: 12782719
interleukin 10; Fc receptor; signal transduction; Jak-Stat; macrophage
24.  Can SOCS make arthritis better? 
Journal of Clinical Investigation  2003;111(6):795-797.
PMCID: PMC153773  PMID: 12639982
25.  Epigenetic regulation of macrophage polarization and function 
Trends in immunology  2012;34(5):216-223.
Macrophage polarization refers to development of a specific phenotype important for tissue homeostasis or host defense in response to environmental cues. Environmental factors that induce macrophage polarization include cytokines and microbial factors produced by pathogens or commensal microbiota. Signaling pathways utilized by these polarizing factors have been well characterized, but it is less clear how signals are converted into complex and sustained patterns of gene expression, and how macrophages are reprogrammed during polarization to alter their responses to subsequent environmental challenges. Emerging evidence, reviewed here, suggests an important role for epigenetic mechanisms in modulating and transmitting signals during macrophage polarization and reprogramming. Deeper understanding of epigenetic regulation of macrophage phenotype will enable development of gene-specific therapeutic approaches to enhance host defense while preserving tissue integrity and preventing chronic inflammatory diseases.
PMCID: PMC3647003  PMID: 23218730
chromatin; epigenetics; macrophage; signaling; transcription

Results 1-25 (50)