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Yuejuan Zheng,
Ziyi Guo,
Weigang He,
Yang Yang,
Yuhu Li,
Aoxiang Zheng,
Ping Li,
Yan Zhang,
Jinzhu Ma,
Mingyue Wen,
Muyi Yang, Huazhang An,
Guang Ji,
Yizhi Yu
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ABSTRACT: Sepsis and its derivative endotoxic shock are still serious conditions with high mortality in the intensive care unit. The mechanisms that ensure the balance of proinflammatory cytokines and anti-inflammatory cytokine production are of particular importance. As an active α- and β-adrenergic agonist, ephedrine hydrochloride (EH) is a widely used agent for cardiovascular diseases, especially boosting blood pressure. Here we demonstrate that EH increased Toll-like receptor 4 (TLR4)-mediated production of interleukin 10 (IL-10) through p38 MAPK activation. Simultaneously, EH negatively regulated the production of proinflammatory cytokines. Consistently, EH increased lipopolysaccharide (LPS)-induced serum IL-10 and inhibited tumor necrotic factor-α (TNFα) production in vivo. As a result, EH treatment protected mice from endotoxic shock by lethal LPS challenge. In brief, our data demonstrated that EH could contribute to immune homeostasis by balancing the production of proinflammatory cytokines and anti-inflammatory cytokine in TLR4 signaling. This study provides a potential usage of EH in autoimmunologic diseases or other severe inflammations.
International immunopharmacology 03/2012; 13(1):46-53. · 2.21 Impact Factor
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Nature Immunology 03/2011; 12(3):271. · 26.01 Impact Factor
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ABSTRACT: Intracellular nucleic acid sensors detect microbial RNA and DNA and trigger the production of type I interferon. However, the cytosolic nucleic acid-sensing system remains to be fully identified. Here we show that the cytosolic nucleic acid-binding protein LRRFIP1 contributed to the production of interferon-beta (IFN-beta) induced by vesicular stomatitis virus (VSV) and Listeria monocytogenes in macrophages. LRRFIP1 bound exogenous nucleic acids and increased the expression of IFN-beta induced by both double-stranded RNA and double-stranded DNA. LRRFIP1 interacted with beta-catenin and promoted the activation of beta-catenin, which increased IFN-beta expression by binding to the C-terminal domain of the transcription factor IRF3 and recruiting the acetyltransferase p300 to the IFN-beta enhanceosome via IRF3. Therefore, LRRFIP1 and its downstream partner beta-catenin constitute another coactivator pathway for IRF3-mediated production of type I interferon.
Nature Immunology 06/2010; 11(6):487-94. · 26.01 Impact Factor
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ABSTRACT: RIG-I-like helicases and TLRs are critical sensors in the induction of type I IFN and proinflammatory cytokines to initiate innate immunity against invading pathogens. However, the mechanisms for the full activation of TLR and RIG-I-triggered innate response remain to be fully investigated. Grb2-associated binder 1 (Gab1), a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors, however, whether and how Gab1 is required for TLR and RIG-I-triggered innate responses remain unknown. In this study, we demonstrated that Gab1 significantly enhances TLR4-, TLR3-, and RIG-I-triggered IL-6, IL-1beta, and IFN-alpha/beta production in macrophages. Gab1 knockdown in primary macrophages or Gab1 deficiency in mouse embryonic fibroblasts significantly suppresses TLR3/4- and RIG-I-triggered production of IL-6, IL-1beta, and IFN-alpha/beta. Consistently, Gab1 deficiency impairs vesicular stomatitis virus (VSV) infection-induced IFN-alpha/beta production. In addition to promoting both MyD88- and TLR/IL-1 receptor domain-containing adaptor protein inducing IFN-beta-dependent MAPKs and NF-kappaB activation, Gab1 enhances PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection. Accordingly, Gab1 inhibits VSV replication and VSV infection-induced cell damage by inducing type I IFNs and IFN-inducible gene expression via PI3K/Akt pathway. Therefore, Gab1 is needed for full activation of TLR3/4- and RIG-I-triggered innate responses by promoting activation of PI3K/Akt, MAPKs, and NF-kappaB pathways.
The Journal of Immunology 06/2010; 184(11):6447-56. · 5.79 Impact Factor
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ABSTRACT: Toll-like receptors sense invading pathogens by recognizing a wide variety of conserved pathogen-associated molecular patterns (PAMPs). The members of TLR family selectively utilize adaptor proteins MyD88, TRIF, TIRAP and TRAM to activate overlapping but distinct signal transduction pathways which trigger production of different panels of mediators such as proinflammatory cytokines and type I interferon. These mediators not only control innate immunity but also direct subsequently developed adaptive immunity. TLR activation is strictly and finely regulated at multiple levels of the signal transduction pathways.
Science China. Life sciences 01/2010; 53(1):34-43. · 2.02 Impact Factor
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ABSTRACT: Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I (RIG-I)- like helicases, cells are activated to produce type I IFN and proinflammatory cytokines. These pathways are tightly regulated by host to prevent inappropriate cellular response, but viruses can down-regulate these pathways for their survival. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling, especially the RIG-I pathway, attract much attention. However, there is no report about negative regulation of RIG-I antiviral pathway by microRNAs (miRNA) to date. We found that vesicular stomatitis virus (VSV) infection up-regulated miR-146a expression in mouse macrophages in TLR-myeloid differentiation factor 88-independent but RIG-I-NF-kappaB-dependent manner. In turn, miR-146a negatively regulated VSV-triggered type I IFN production, thus promoting VSV replication in macrophages. In addition to two known miR-146a targets, TRAF6 and IRAK1, we proved that IRAK2 was another target of miR-146a, which also participated in VSV-induced type I IFN production. Furthermore, IRAK1 and IRAK2 participated in VSV-induced type I IFN production by associating with Fas-associated death domain protein, an important adaptor in RIG-I signaling, in a VSV infection-inducible manner. Therefore, we demonstrate that miR-146a, up-regulated during viral infection, is a negative regulator of the RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1, and IRAK2.
The Journal of Immunology 09/2009; 183(3):2150-8. · 5.79 Impact Factor
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ABSTRACT: Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC.
Journal of Biological Chemistry 05/2009; 284(24):16183-90. · 4.77 Impact Factor
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ABSTRACT: Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study
showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting cell cycle
and inducing apoptosis. HCC cells are resistant to apoptotic induction by TRAIL, so, new therapeutic approaches have been
explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance
the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive
activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation
was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of Akt/Hdm2
pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1
signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced
apoptosis, while, Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells
and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent
on p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together,
Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating
p53 dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to
improve the therapeutic efficacy of TRAIL-resistant HCC.
Journal of Biological Chemistry 04/2009; · 4.77 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) are primary sensors to detect conserved patterns on microorganisms, thus acting as the important components of innate immunity against invading pathogens. Protein tyrosine phosphatase-1B (PTP1B) has been shown to be a critical negative regulator of insulin pathway and other cellular signaling, however, whether and how PTP1B regulates TLR-triggered innate response remain to be investigated. We report here that PTP1B can markedly decrease TNF-alpha, IL-6 and IFN-beta production by macrophages stimulated with LPS, CpG ODN, or Poly I:C. Accordingly, knockdown of endogenous PTP1B expression increases production of TNF-alpha, IL-6 and IFN-beta in macrophages stimulated with TLR ligands. Phosphatase activity-disrupted mutant PTP1B cannot inhibit TLR-triggered production of proinflammatory cytokines and IFN-beta, indicating PTP1B exerts its suppressive activity in phosphatase-dependent manner. PTP1B inhibits TLR ligands-induced activation of MAPKs, NF-kappaB, and IRF3, furthermore, co-transfection of PTP1B inhibits both MyD88- and TRIF-induced transcription of TNF-alpha and IFN-beta reporter genes in a dose-dependent manner. In addition, PTP1B inhibits LPS-induced Tyk2 and STAT1 activation. Therefore, we demonstrate that phosphatase PTP1B is a physiological negative regulator of TLR signaling via suppression of both MyD88- and TRIF-dependent production of proinflammatory cytokine and IFN-beta in macrophages. Our results provide new mechanistic explanation for negative regulation TLR response and suggest PTP1B as a potential target for the intervention of the inflammatory diseases.
Molecular Immunology 09/2008; 45(13):3545-52. · 2.90 Impact Factor
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ABSTRACT: Dendritic cells (DCs) play crucial roles in linking innate immunity and adaptive immunity, thus being regarded as one of the important targets of immunosuppressant. Natural small molecule products isolated from plants, such as fungal metabolites, have been shown to be effective in the treatment of cancer, inflammation and autoimmune diseases. Albaconol is a new kind of prenylated resorcinols isolated from the fruiting bodies of the inedible mushroom Albatrellus confluens, and has been shown to inhibit tumor cell growth. Considering that most of small molecule compounds with antitumor activity always exert immunosuppressive effect, so we wonder whether albaconol could inhibit maturation and antigen presentation of DCs, thus acting as immunosuppressant. Here we demonstrate that albaconol significantly inhibits LPS-induced production of proinflammatory cytokines TNF-alpha, IL-6, IL-1beta, and expression of MHC-II and co-stimulatory molecules by DCs. Furthermore, albaconol markedly inhibits T cell-stimulating capacity of DCs and DCs-initiated antigen-specific T cell response, indicating albaconol can inhibit phenotypic and functional maturation of DCs. Inhibition of LPS-induced NF-kappaB activation may contribute to the above immunosuppressive or anti-inflammatory activities of albaconol. Therefore, our results suggest that natural small molecule albaconol may be a potential immunosuppressive and anti-inflammatory agent through suppressing DCs function via impairment of NF-kappaB activation.
International Immunopharmacology 09/2008; 8(8):1103-11. · 2.38 Impact Factor
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ABSTRACT: Unbalanced production of proinflammatory cytokines and type I interferons in immune responses may lead to immunopathology; thus, the mechanisms that ensure the beneficial production of proinflammatory cytokines and type I interferons are of particular importance. Here we demonstrate that the phosphatase SHP-1 negatively regulated Toll-like receptor-mediated production of proinflammatory cytokines by inhibiting activation of the transcription factor NF-kappaB and mitogen-activated protein kinase. Simultaneously, SHP-1 increased the production of type I interferon mediated by Toll-like receptors and the helicase RIG-I by directly binding to and inhibiting activation of the kinase IRAK1. Our data demonstrate that SHP-1 contributes to immune homeostasis by balancing the production of proinflammatory cytokines and type I interferons in the innate immune response.
Nature Immunology 06/2008; 9(5):542-50. · 26.01 Impact Factor
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ABSTRACT: Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain-containing adapter, inducing interferon (IFN)-beta-dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha, IL-6, nitric oxide, and IFN-beta, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor kappaB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1-positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.
Blood 08/2007; 110(3):962-71. · 9.90 Impact Factor
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ABSTRACT: Dendritic cells (DCs) and chemokines are important mediators linking innate and adaptive immunity on activation by Toll-like receptor (TLR) agonists. We previously identified a kind of regulatory DC subset (diffDCs) that differentiated from mature DCs under splenic stroma and that inhibited T-cell proliferation. The responsiveness of such regulatory DCs to TLR agonists and their pattern of chemokine production remain to be determined. Here, we report that the regulatory DCs secrete a higher level of CXCR3 chemokine IFN-gamma-induced protein-10 (IP-10) than immature DCs (imDCs), and more IP-10 is produced after stimulation with TLR-2, -4, -3, and -9 ligands. Blockade of IFN-alpha/beta inhibits IP-10 production by TLR agonist-activated regulatory DCs. We show that the increased IRF-3 and IFN-beta-induced STAT1 activation are responsible for the autocrine IFN-beta-dependent preferential production of IP-10 by regulatory DCs. In addition, stimulation with recombinant mouse IFN-alpha/beta induces more IP-10 production in regulatory DCs than that in imDCs. Moreover, the regulatory DCs selectively recruit more Th1 cells through IP-10 and inhibit Th1 proliferation. Our results demonstrate a new manner for regulatory DCs to down-regulate T-cell response by preferential IP-10 production and inhibition of recruited Th1 cell proliferation.
Blood 05/2007; 109(8):3308-15. · 9.90 Impact Factor
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ABSTRACT: Fever influences multiple parameters of the immune response. However, the mechanisms by which fever manipulates immune response remain undefined. Here we present the evidences that fever range hyperthermia differentially regulates immune response to lipopolysaccharide (LPS) and lipoteichoic acids (LTA) through modulating Toll-like receptor (TLR) signaling. Pretreatment with 39.5 degrees C temperature enhanced LPS, but not LTA, induced NF-kappaB activation and TNF-alpha, IL-6 production in human macrophages. Consistently, expression of TLR4, but not TLR2, was up-regulated by 39.5 degrees C treatment. The increase in LPS-induced cytokine production was inhibited by TLR4-blocking antibody, indicating the enhancement of LPS-induced cytokine production by 39.5 degrees C pretreatment was TLR4-dependent. Pretreatment of mice with 39.5 degrees C temperature also enhanced LPS, but not LTA, induced TNF-alpha and IL-6 production in vivo. These results support the concept that fever range hyperthermia might activate innate immune response by promoting TLR4 expression and signaling, providing a possible mechanistic explanation for the function of fever in regulating innate immune responses.
Immunology Letters 03/2007; 108(2):137-42. · 2.53 Impact Factor
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ABSTRACT: Fever improves survival and shortens disease duration in microbial infections. However, the mechanisms of these beneficial responses still remain elusive. Toll-like receptors (TLRs) play important roles in sensing microbes invading and therefore we hypothesized that fever range temperature may enhance responsiveness of dendritic cells (DCs) to lipopolysaccharide (LPS) by promoting TLR4 expression and signaling. In this study, we found that pretreatment of DCs with 39.5 degrees C temperature can up-regulate TLR4 expression in DCs and enhances LPS-induced DC production of interleukins (IL) IL-6, IL-10 and IL-12 but not tumor necrosis factor alpha (TNF-alpha). Blockade of the autocrine action of IL-10 could increase LPS-induced TNF-alpha and IL-12 production in DCs. Further experiments confirmed that TLR4 ligation activates extracellular signal-regulated kinase (ERK), p38, and nuclear factor-kappaB pathways more potently in DCs pretreated with 39.5 degrees C. We conclude that fever range temperature can promote TLR4 expression and signaling in DCs, leading to enhancement of immune responses to inflammatory stimuli. These results might reveal a possible mechanistic explanation for the significance of fever in activating innate immune responses.
Life Sciences 02/2007; 80(4):307-13. · 2.53 Impact Factor
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Huazhang An,
Wei Zhao,
Jin Hou,
Yan Zhang,
Yun Xie,
Yuejuan Zheng,
Hongmei Xu,
Cheng Qian,
Jun Zhou,
Yizhi Yu,
Shuxun Liu,
Gensheng Feng,
Xuetao Cao
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ABSTRACT: The Toll-like receptor 3 (TLR3) and TLR4-signaling pathway that involves the adaptor protein TRIF activates type I interferon (IFN) and proinflammatory cytokine expression. Little is known about how TRIF pathway-dependent gene expression is regulated. SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a widely expressed cytoplasmic tyrosine phosphatase. Here we demonstrate that SHP-2 negatively regulated TLR4- and TLR3-activated IFN-beta production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated proinflammatory cytokine IL-6 and TNF-alpha production. SHP-2 inhibited poly(I:C)-induced cytokine production by a phosphatase activity-independent mechanism. C-terminal domain of SHP-2 directly bound TANK binding kinase (TBK1) by interacting with the kinase domain of TBK1. SHP-2 deficiency increased TBK1-activated IFN-beta and TNF-alpha expression. TBK1 knockdown inhibited poly(I:C)-induced IL-6 production in SHP-2-deficient cells. SHP-2 also inhibited poly(I:C)-induced activation of MAP kinase pathways. These results demonstrate that SHP-2 specifically negatively regulate TRIF-mediated gene expression in TLR signaling, partially through inhibiting TBK1-activated signal transduction.
Immunity 01/2007; 25(6):919-28. · 21.64 Impact Factor
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ABSTRACT: Regulatory dendritic cells (DCs) play an important role in maintaining peripheral tolerance or immune homeostasis. Our previous study demonstrated that mature DCs could be driven by splenic stroma to proliferate and differentiate into a novel subset of regulatory DCs (diffDCs) displaying a Th2-biased cytokine profile. However, the underlying mechanisms for the unique cytokine profile of diffDCs and how diffDCs regulate the innate and adaptive immunity in response to toll-like receptor (TLR) agonists remain unclear. Here, we report that unlike immature DCs, diffDCs secrete more interleukin 10 (IL-10) but little IL-12p70 in response to lipopolysaccharide (LPS) or other TLR agonists. Up-regulation of extracellular signal-regulated kinase (ERK1/2) activation was shown to be responsible for IL-10 preferential production, and suppression of p38 activation was for impaired IL-12p70 production in diffDCs. Interestingly, LPS treatment could not reverse the inhibitory effect of diffDCs on the proliferation of antigen-specific CD4+ T cells. However, diffDCs could activate natural killer (NK) cells through diffDC-derived IL-10, and even more markedly after stimulation of TLR agonists. These diffDC-activated NK cells could in turn kill surrounding diffDCs. Our results illuminate signal pathways for the unique cytokine profile of diffDCs, and diffDCs can exert their regulatory function even after inflammatory stimuli, thus reflecting one way for strict regulation of immune response.
Blood 11/2006; 108(7):2307-15. · 9.90 Impact Factor
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ABSTRACT: Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) plays important roles in negatively regulating the activation of immune cells primarily via the phosphoinositide 3-kinase (PI-3K) pathway by catalyzing the PI-3K product PtdIns-3,4,5P3 (phosphatidylinositol-3,4,5-triphosphate) into PtdIns-3,4P2. However, the role of SHIP1 in Toll-like receptor 4 (TLR4)-mediated lipopolysaccharide (LPS) response remains unclear. Here we demonstrate that SHIP1 negatively regulates LPS-induced inflammatory response via both phosphatase activity-dependent and -independent mechanisms in macrophages. SHIP1 becomes tyrosine phosphorylated and up-regulated upon LPS stimulation in RAW264.7 macrophages. SHIP1-specific RNA-interfering and SHIP1 overexpression experiments demonstrate that SHIP1 inhibits LPS-induced tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production by negatively regulating the LPS-induced combination between TLR4 and myeloid differentiation factor 88 (MyD88); activation of Ras (p21(ras) protein), PI-3K, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase (JNK); and degradation of IkappaB-alpha. SHIP1 also significantly inhibits LPS-induced mitogen-activated protein kinase (MAPK) activation in TLR4-reconstitited COS7 cells. Although SHIP1-mediated inhibition of PI-3K is dependent on its phosphatase activity, phosphatase activity-disrupted mutant SHIP1 remains inhibitory to LPS-induced TNF-alpha production. Neither disrupting phosphatase activity nor using the PI-3K pathway inhibitor LY294002 or wortmannin could significantly block SHIP1-mediated inhibition of LPS-induced ERK1/2, p38, and JNK activation and TNF-alpha production, demonstrating that SHIP1 inhibits LPS-induced activation of MAPKs and cytokine production primarily by a phosphatase activity- and PI-3K-independent mechanism.
Blood 07/2005; 105(12):4685-92. · 9.90 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) play a critical role in innate immunity and TLR9 is essential for CpG ODN signaling. As "dangerous signal", heat shock may regulate immune response. However, little is known about TLRs expression and signaling after heat shock. In this study, we investigated regulation of TLR9 expression and function in human B cell line RPMI8226 by heat shock. We demonstrated that TLR9 expression was up-regulated remarkably following heat shock. Coincidently, CpG ODN stimulation significantly increased IL-6 production and up-regulated expressions of MHC I, MHC II and CD86 by heat-shocked B cells. Heat shock activated ERK and NF-kappaB signal pathways, and pretreatment of B cells with specific inhibitors of ERK or NF-kappaB signal pathways inhibited heat shock-induced up-regulation of TLR9 expression. These results demonstrated that heat shock promotes TLR9 expression and signaling through activation of ERK and NF-kappaB signal pathways in B cells, suggesting that heat shock might modulate host immune response by regulating TLR expression.
Immunology Letters 05/2005; 98(1):153-9. · 2.53 Impact Factor
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ABSTRACT: Summary Heat stress can alert innate immunity by inducing stress proteins such as heat-shock proteins (HSPs). However, it remains unclear whether heat stress affects the activation of antigen-presenting cell (APC) in response to pathogen-associated molecule patterns (PAMPs) by directly regulating pathogen recognition receptors (PRRs). As an important kind of PRRs, Toll-like receptors (TLRs) play critical roles in the activation of immune system. In this study, we demonstrated that heat shock up-regulated the expression of HSP70 as well as TLR2 and TLR4 in monocytes. The induction of TLRs was prior to that of HSP70, which suggesting the up-regulation of TLR2 and TLR4 might be independent of the induction of HSP70. Heat shock activated p38 kinase, extracellular signal-related kinase (ERK) and nuclear factor-kappa B (NF-kappaB) signal pathways in monocytes. Pretreatment with specific inhibitor of p38 kinase, but not those of ERK and NF-kappaB, inhibited heat shock-induced up-regulation of TLR2 and TLR4. This indicates that p38 pathway takes part in heat shock-induced up-regulation of TLR2 and TLR4. Heat shock also increased lipoteichoic acid- or lipopolysaccharide-induced interleukin-6 production by monocytes. These results suggest that the p38 kinase-mediated up-regulation of TLR2 and TLR4 might be involved in the enhanced response to PAMP in human monocytes induced by heat shock.
Immunology 05/2005; 114(4):522-30. · 3.32 Impact Factor
