N-乙酰半胱氨酸对脂多糖诱导的小鼠肝MAPK磷酸化的影响

目的： 探讨N-乙酰半胱氨酸（NAC）对脂多糖（LPS）诱导的肝MAPK磷酸化的影响。方法: 雄性昆明种小鼠54只随机分为对照组(n=6)：0.9 % NaCl 0.2 mL ip；LPS组（n=24）：LPS 5 mg ip；NAC+LPS组（n=24）：NAC 150 mg·kg-1·d-1ip，连续3 d；第3 d NAC灌胃后1 h时，LPS 5 mg ip。将小鼠分别在注射LPS或生理盐水后0.5 h、1 h、2 h和6 h时，在戊巴比妥钠麻醉下开腹取肝，测定肝MDA和还原型谷胱甘肽（GSH）含量；Western blotting方法测定肝脏MEK1/2、ERK1/2、p38MAPK磷酸化水平，放免法测定肝TNF-α含量。结果: NAC预处理使肝MDA含量明显下降，使肝GSH含量升高。NAC预处理显著抑制了LPS所致的肝MEK1/2、ERK1/2、p38MAPK磷酸化，同时使肝TNF-α水平显著降低。结论: 在LPS诱导的急性肝损伤过程中，活性氧（ROS）在激活MAPK信号转导中起重要作用。NAC通过其抗氧化作用部分抑制了LPS诱导的MAPK磷酸化，使TNF-α生成减少，从而发挥抗损伤作用。     

封闭枯否细胞对LPS诱导激活丝裂原活化蛋白激酶的影响

目的： 利用小鼠LPS血症模型，探讨封闭枯否细胞（KCs）对LPS诱导MAPK信号转导通路的影响。方法： 雄性昆明种小鼠在注射LPS（5 mg/kg）前48 h及24 h，分别静脉注射GdCl₃（10 mg/kg）或等量的生理盐水，于LPS或生理盐水注射后30 min，分别取出肝脏或分离KCs；体外培养小鼠KCs经GdCl₃（100 μmol/L）预处理1 h，加入含LPS（100 μg/L）的DMEM培养基继续孵育30 min，分别检测肝脏及体内外KCs ERK1/2、p38MAPK蛋白表达和磷酸化水平，及GdCl₃对KCs吞噬、分泌功能的影响。结果： GdCl₃可抑制LPS 诱导KCs活化和TNF-α分泌，但不能抑制LPS诱导KCs或肝脏ERK1/2、p38MAPK磷酸化，也不能影响ERK1/2、p38MAPK蛋白表达，KCs 经GdCl₃单独短时间处理（1 h），可使其少量分泌TNF-α。结论： 封闭KCs并不能通过调节细胞内ERK1/2、p38MAPK信号转导途径，抑制LPS诱导的KCs活化及TNF-α释放，而可能是通过其它信号转导途径（JNK、NF-кB、GPCR等）间的相互作用减轻肝损伤。     

Chikusetsusaponin V attenuates lipopolysaccharide-induced liver injury in mice

Chikusetsusaponin V (CsV), a saponin from Panax japonicus, has been reported to inhibit inflammatory responses in lipopolysaccharide (LPS)-induced macrophage cells. However, whether CsV could alleviate LPS-induced liver injury in vivo and the potential mechanisms involved remain unclear. In the present study, we investigated the anti-inflammatory effects of CsV on LPS-induced acute liver injury in mice and further explored the potential mechanisms involved. Our results showed that CsV significantly attenuated elevation of alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and improved liver histopathological changes in LPS-induced mice. In addition, CsV decreased serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels and inhibited mRNA expressions of inducible nitric oxide synthase (iNOS), TNF-α and IL-1β in LPS challenged mice. Furthermore, CsV inhibited nuclear factor kappa B (NF-κB) activation by downregulating phosphorylated NF-κB, IκB-α, ERK, c-Jun N-terminal kinase (JNK) and p38 levels in the liver tissue, which ultimately decreased nucleus NF-κB protein level. In conclusion, our data suggested that CsV could be a promising drug for preventing LPS challenged liver injury since it attenuated LPS-induced inflammatory responses, partly via inhibiting NF-κB and MAPK signaling pathways.     

A G protein-associated ERK pathway is involved in LPS-induced proliferation and a PTK-associated p38 MAPK pathway is involved in LPS-induced differentiation in resting B cells

We, previously, showed that PKC-dependent ERK/p38 MAPK activation was inhibited by treating the resting B cell line 38B9 with an anti-MHC class II antibody. Further studies in this work demonstrated that PKA was involved in lipopolysaccharide (LPS)-induced proliferation of the cells, such that the PKC inhibitor activated PKA with concomitant LPS-induced proliferation but not IgG secretion. Consequently, the PKA inhibitor down-regulated ERK and p38 MAPK, and decreased cell proliferation. In addition, the treatment of LPS-stimulated 38B9 cells with PTK inhibitor reduced PKC- and PKA-dependent p38 MAPK activation and reduced the level of IgG secretion rather than the level of proliferation. However, the treatment of LPS-stimulated 38B9 cells with pertussis toxin (PTX), an inhibitor for the G protein-coupled receptor, inhibited the activation of both PKC- and PKA-dependent ERK and significantly reduced LPS-induced proliferation but not IgG secretion. Furthermore, ERK and p38 MAPK inhibitors reduced LPS-induced proliferation and differentiation, respectively, in 38B9 cells in a dose-dependent manner. These results suggest that LPS-induced proliferation of resting B cells is mainly mediated through a G protein-associated PKA/PKC-dependent ERK pathway and that a PTK-associated PKC/PKA-dependent p38 MAPK pathway is mostly involved in LPS-induced differentiation of the resting B cells.     

Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines

Neutrophils are an important cellular source of proinflammatory mediators, whose regulation may be of potential benefit for the treatment of a number of inflammatory diseases. However, the mechanisms of lipopolysaccharide (LPS)-induced neutrophil activation and its regulation by anti-inflammatory cytokines have not yet been fully elucidated. Recent studies have revealed that mitogen-activated protein kinases (MAPK) play a crucial role in the generation of proinflammatory mediators in some cell types. Therefore, we conducted this study to determine whether MAPK activation could be involved in prostaglandin E(2) (PGE(2)) production and cyclooxygenase (COX)-2 expression in LPS-stimulated human neutrophils. PD98059 (MEK1 inhibitor) and SB203580 (p38(MAPK) inhibitor) reduced PGE(2) production as well as COX-2 expression in LPS-stimulated neutrophils. In addition, both extracellular signal-regulated protein kinase (ERK) and p38(MAPK) were phosphorylated and activated in time- and dose-dependent manners. Since we previously showed that IL-10 and IL-4 similarly inhibited COX-2 expression in LPS-stimulated neutrophils, we next tested the effects of IL-10 and IL-4 on the phosphorylation and activation of both kinases. IL-10 inhibited the phosphorylation and activation of p38(MAPK), but not ERK. In addition, IL-4 caused a marginal inhibition in the activation of p38(MAPK). Taken together, these results suggest that both ERK and p38(MAPK) pathways are involved in LPS-induced COX-2 expression and PGE(2) production in neutrophils, and IL-10 and IL-4 inhibit neutrophil prostanoid synthesis by down-regulating the activation of p38(MAPK).     

Elevated Reactive Oxygen Species but not Glutathione Regulate Mercury Resistance to AML-2/DX100 Cells

The multidrug resistance-associated protein (MRP1) mediates cellular efflux of various xenobiotics and cellular resistance to heavy metals. Previously we reported that MRP1 mediates resistance to mercury exposure and possible mechanism mediating MRP1 expression after mercury exposure. This study was designed to investigate the role of reactive oxygen species (ROS) and glutathione on the resistance of AML-2/DX100 cells to mercuric chloride. The MRP1 overexpressing cells (AML-2/DX100) cells showed less scavenging activity to ROS induced by mercury while no difference in the basal glutathione levels between AML-2/WT and AML-2/DX100 cells. Mercury induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) but not c-jun-N-terminal kinase in AML-2/DX100 cells. The specific inhibitor for p38 MAPK and ERK, and antioxidant decreased the production of MRP1 and therefore resistance of AML-2/DX100 cells against mercury exposure. These results suggest that induction of ROS and downstream p38 MAPK and ERK were involved in the resistance of cells to mercury by expression MRP1 in AML-2/DX100 cells.     

Elevated reactive oxygen species but not glutathione regulate mercury resistance to AML-2/DX100 cells

The multidrug resistance-associated protein (MRP1) mediates cellular efflux of various xenobiotics and cellular resistance to heavy metals. Previously we reported that MRP1 mediates resistance to mercury exposure and possible mechanism mediating MRP1 expression after mercury exposure. This study was designed to investigate the role of reactive oxygen species (ROS) and glutathione on the resistance of AML-2/DX100 cells to mercuric chloride. The MRP1 overexpressing cells (AML-2/DX100) cells showed less scavenging activity to ROS induced by mercury while no difference in the basal glutathione levels between AML-2/WT and AML-2/DX100 cells. Mercury induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) but not c-jun-N-terminal kinase in AML-2/DX100 cells. The specific inhibitor for p38 MAPK and ERK, and antioxidant decreased the production of MRP1 and therefore resistance of AML-2/DX100 cells against mercury exposure. These results suggest that induction of ROS and downstream p38 MAPK and ERK were involved in the resistance of cells to mercury by expression MRP1 in AML-2/DX100 cells.     

Protective effect of glutathione against lipopolysaccharide-induced inflammation and mortality in rats

Objective To investigate protective effect of glutathione (GSH) against lipopolysaccharide (LPS)-induced inflammation and mortality in rats. Methods Male Sprague-Dawley rats were injected intraperitoneally (i. p.) with GSH (40 mg/kg) 30 min prior to LPS injection (20 mg/kg). Animal survival rate and the production of nitric oxide in serum were measured. Morphology of lung was observed using hematoxylin and eosin staining. Western blotting was used to assess the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the phosphorylation of p38 in rat peritoneal macrophages. Results GSH significantly decreased LPS-induced mortality, inhibited serum NO production and eliminated lung histological injury. Furthermore, GSH inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and the phosphorylation of p38 in LPS-stimulated rat peritoneal macrophages. Conclusions These results indicated that GSH suppressed LPS-induced systemic inflammatory response in rats and p38 MAPK signal pathway was involved in this process. Received 20 March 2006; returned for revision 21 May 2006; returned for final revision 11 June 2006; accepted by M. Katori 7 July 2006     

Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms

Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen-activated protein kinases [MAPK; e.g., p38 and extracellular signal-regulated kinase (ERK)1/2] for endotoxin-induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin-mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS-induced TNF production but only partially attenuated LPS-induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS-induced TNF production but failed to inhibit LPS-induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS-induced activation of p38 MAPK and yet, still significantly attenuated LPS-mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms.     

Gö6976 inhibits LPS-induced microglial TNFalpha release by suppressing p38 MAP kinase activation

Microglial responses to endotoxin, including the synthesis of inflammatory factors, contribute to gliosis and neuron degeneration in cultured brain tissue. We have previously shown that G?6976, a protein kinase C (PKC) inhibitor, suppressed the lipopolysaccharide (LPS)-induced production of inflammatory factors in microglia and afforded marked protection of neurons from glia-mediated cytotoxicity. The purpose of this study was to identify the signal transduction pathway underlying the neuroprotective effect of G?6976. G?6976 suppressed the LPS-induced release of tumor necrosis factor alpha (TNFalpha) in the microglial cell line, BV2. We show in this study the inhibitory effect of G?6976 on TNFalpha release occurring through suppression of p38 mitogen-activated protein kinase (MAPK) phosphorylation and not through a PKC mechanism. While G?6976 did not inhibit the activity of p38 MAPK directly, it did suppress its activation by phosphorylation, indicating the target of action of G?6976 is a signaling event upstream of p38 MAPK. Although G?6976 is considered a selective inhibitor of certain PKC isozymes, suppression of TNFalpha production was not mediated through inhibition of PKC activity. G?6976 appears to play a novel role in neuroprotection by suppressing the release of pro-inflammatory factors by inhibiting the activation of p38 MAPK in microglia, rather than a PKC isoform.     

三七皂苷Rg1抑制脂多糖诱导小胶质细胞激活的机制研究

目的:探讨中药有效成分三七皂苷Rg1(Ginsenoside Rg1,Rg1)对抑制脂多糖(lipopolysaccharide,LPS)诱导的小胶质细胞株BV-2细胞激活的机制。方法:用LPS刺激BV-2细胞构建激活模型,采用四甲基偶氮唑蓝比色法(MTT)检测Rg1对BV-2细胞的活力影响,蛋白质免疫印迹(Western Blot)方法检测不同浓度Rg1(10、20和40μmol/L)对磷酸化的核因子-κB抑制蛋白-α(inhibitorκB-α,IκB-α)和反应结合蛋白(cAMP-responseelement binding protein,CREB)以及促分裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs)家族的细胞外信号调节激酶(extracellular signal-regulated kinase 1/2,ERK1/2)、c-Jun氨基端激酶(c-Jun N-terminal kinase,JNK)和p38促分裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)等细胞信号通路蛋白的表达及其变化规律。结果:不同浓度的Rg1明显抑制了LPS诱导的磷酸化IκB-α和CREB蛋白表达以及MAPKs通路(ERK1/2,JNK,p38 MAPK)磷酸化蛋白表达,并且对p38 MAPK表达的影响呈剂量依赖性。结论:Rg1可能通过抑制MAPKs的磷酸化来调控LPS诱导的小胶质细胞株BV-2细胞激活,发挥其神经抗炎的作用。     

Suppressing LPS-induced early signal transduction in macrophages by a polyphenol degradation product: a critical role of MKP-1

Macrophages represent the first defense line against bacterial infection and therefore, play a crucial role in early inflammatory response. In this study, we investigated the role of MAPKs and MKP-1 activation in regulation of an early inflammatory response in RAW 264.7 macrophage cells. We induced the inflammatory response by treating the macrophages with LPS and inhibited an early inflammatory response by using ferulaldehyde, a water-soluble end-product of dietary polyphenol degradation that we found previously to exert its beneficial anti-inflammatory effects during the early phase of in vivo inflammation. We found that LPS-induced ROS and nitrogen species formations were reduced by ferulaldehyde in a concentration-dependent manner, and ferulaldehyde protected mitochondria against LPS-induced rapid and massive membrane depolarization. LPS induced early suppression of MKP-1, which was accompanied by activation of JNK, ERK, and p38 MAPK. By reversing LPS-induced early suppression of MKP-1, ferulaldehyde diminished MAPK activation, thereby inhibiting NF-κB activation, mitochondrial depolarization, and ROS production. Taken together, our data suggest that ferulaldehyde exerts its early anti-inflammatory effect by preserving the mitochondrial membrane integrity and shifting the expression of MKP-1 forward in time in macrophages.     

Different involvement of the MAPK family in inflammatory regulation in human pulmonary microvascular endothelial cells stimulated with LPS and IFN-γ

Pulmonary endothelial injury is central in the pathogenesis of acute lung injury (ALI). The MAPK signaling cascades are generally thought to be involved in the molecular mechanism underlying the ALI development, but their roles in pulmonary endothelial injury is poorly understood. We thus examined the involvement of the MAPK family member in inflammatory responses of human pulmonary microvascular endothelial cells (HPMVECs) stimulated with LPS and IFN-γ. HPMVECs were found to exhibit the upregulation of expression of Toll-like receptor 4 by IFN-γ, resulting in potentiation of inflammatory cytokine release by LPS stimulation. All MAPKs, ERK1/2, JNK, and p38, were activated by simultaneous stimulation with LPS/IFN-γ. JNK activation in cells stimulated with LPS/IFN-γ was significantly potentiated by the two different p38 inhibitors, SB203580 and RWJ67657, suggesting the negative regulation of JNK activation by p38 in HPMVECs. The mRNA and protein expression levels of ICAM-1 were eliminated by the JNK inhibitor, suggesting that ICAM-1 expression is positively regulated by JNK. The p38 inhibitor significantly enhanced ICAM-1 expression. ERK1/2 activation was not responsible for the LPS/IFN-γ-induced ICAM-1 upregulation in HPMVECs. THP-1 monocyte adhesion to HPMVECs under LPS/IFN-γ stimulation was inhibited by the JNK inhibitor and enhanced by the p38 inhibitor. We conclude that, in HPMVECs stimulated with LPS/IFN-γ, JNK mediates ICAM-1 expression that can facilitate leukocyte adherence and transmigration, while p38 MAPK negatively regulates the upregulation of ICAM-1 through inhibition of JNK activation.     

Up-regulation of TLR9 gene expression by LPS in mouse macrophages via activation of NF-kappaB, ERK and p38 MAPK signal pathways

Toll-like receptors (TLR) are critical in the activation of macrophages by bacterial products. It has been shown that TLR2 and TLR4 mediate lipopolysaccharide (LPS) and lipoproteins signal transduction, respectively. Regulation of TLR2 and TLR4 expression by LPS was considered to be one of the mechanisms to control the overall responses of immune cells to bacteria. However, little is known about whether the other members of TLR family are regulated by LPS. Recently, TLR9 was demonstrated to be essential for CpG DNA signaling. Given the effective immune modulation by CpG DNA, regulation of TLR9 expression might play important role in controlling the overall responses of immune cells to bacteria. In this study, regulation of TLR9 gene expression in mouse macrophage cell line RAW264.7 by LPS was investigated. Semiquantitative RT-PCR was performed to determine gene expression of TLR9. Following LPS stimulation, TLR9 gene expression was upregulated within 1 h and reached peak level at about 3 h. LPS stimulation activated NF-kappaB, ERK and p38 MAPK signal pathways. Pretreatment of macrophages with inhibitors of NF-kappaB, ERK and p38 MAPK signal pathways inhibited LPS-induced upregulation of TLR9 mRNA expression. Our results demonstrated that LPS stimulation could upregulate gene expression of TLR9 via NF-kappaB, ERK, and p38 MAPK signal pathways in macrophages, indicating that macrophages with increased TLR9 expression induced by LPS might respond to invading bacteria more effectively.     

Magnesium isoglycyrrhizinate attenuates D-galactosamine/lipopolysaccharides induced acute liver injury of rat via regulation of the p38-MAPK and NF-κB signaling pathways

Context: Acute hepatic failure involves in serious inflammatory responses and leads to a high mortality. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-α glycyrrhizic acid (GA) stereoisomer, has been shown anti-inflammatory activity previously.

Objective: This study aimed to investigate the protective effects of MgIG, a hepatocyte protective agent, on D-galactosamine and lipopolysaccharide (D-GaIN/LPS)-induced acute liver injury in rats, and meanwhile explore the molecular mechanism.

Materials and methods: Male Sprague–Dawley (SD) rats were injected with D-GaIN/LPS (800?mg/kgBW/10?μg/kgBW) with or without administration of MgIG (225?mg/kg once 6?h after D-GaIN/LPS injection and MgIG 45?mg/kg twice in another 12?h, intraperitoneal injection). Rats were sacrificed 24?h after D-GaIN/LPS injection, the blood and liver samples were collected for future inflammation and hepatotoxicity analyses.

Results: MgIG significantly inhibited D-GaIN/LPS-induced inflammatory cytokines production and hepatotoxicity as indicated by both diagnostic indicators of liver damage [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels] and histopathological analysis. Western blot analysis demonstrated that MgIG significantly decreased p38-mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation induced by D-GaIN/LPS.

Conclusion: The results indicated that the protective effects of MgIG on D-GaIN/LPS-induced acute liver injury might be correlated with its capacity to regulate the p38-MAPK and NF-κB signaling pathways.     

Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Production by Human Monocytes Involves the Raf-1/MEK1-MEK2/ERK1-ERK2 Pathway

During gram-negative sepsis, human monocytes are triggered to produce large quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have identified signal transduction pathways that are activated by LPS, including activation of nuclear factor-kappaB (NF-kappaB) and activation of mitogen-activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS-induced TNF-alpha production by primary human monocytes has been addressed with PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1. TNF-alpha levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml, were reduced by PD-098059 (50 microM). In addition, PD-098059 also reduced TNF-alpha mRNA expression when cells were stimulated for 1 h with LPS. On the other hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK inhibitor, completely abrogated TNF-alpha levels at nanomolar concentrations. IL-10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09-2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2. Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2 in a time- and concentration (50% effective concentration between 1 and 10 ng of LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50 microM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was prevented by Ro 09-2210. These data further support the view that the ERK signal transduction pathway is causally involved in the synthesis of TNF-alpha by human monocytes stimulated with LPS.     

P38 Mitogen Activated Protein Kinase Is Involved in the Downregulation of Granulocyte CXC Chemokine Receptors 1 and 2 During Human Endotoxemia

Chemokine receptors CXC receptor (CXCR) 1 and 2, and their ligands interleukin (IL)-8 and growth-related oncogene alpha (GRO alpha), are principal regulators of neutrophil activation and migration. To investigate the role of p38 mitogen activated protein kinase (MAPK) in the regulation of CXCR expression during an inflammatory response in vivo, 24 healthy volunteers received an intravenous injection with lipopolysaccharide (LPS) preceded (-3 hr) by a specific p38 MAPK inhibitor (BIRB 796 BS) at a high dose (600 mg) or a low dose (50 mg) or a placebo. The LPS-induced reduction of neutrophil CXCR 1 and 2 expression, as determined by fluorescence-activated cell sorter analysis, was inhibited in volunteers receiving the high dose of the p38 MAPK inhibitor. The kinase inhibitor also dose dependently diminished the LPS-induced rises in plasma IL-8 and GRO alpha levels. These results indicate a principal role for p38 MAPK in regulating factors essential for neutrophil activation and chemotaxis in vivo.     

SOCS1/JAB is a negative regulator of LPS-induced macrophage activation

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4. We show here that the suppressor of cytokine-signaling-1 (SOCS1/JAB) is rapidly induced by LPS and negatively regulates LPS signaling. SOCS1(+/-) mice or SOCS1(-/-) mice with interferon-gamma (IFNgamma)-deficient background were more sensitive to LPS-induced lethal effects than were wild-type littermates. LPS-induced NO(2)(-) synthesis and TNFalpha production were augmented in SOCS1(-/-) macrophages. Furthermore, LPS tolerance, a protection mechanism against endotoxin shock, was also strikingly reduced in SOCS1(-/-) cells. LPS-induced I-kappaB and p38 phosphorylation was upregulated in SOCS1(-/-) macrophages, and forced expression of SOCS1 suppressed LPS-induced NF-kappaB activation. Thus, SOCS1 directly suppresses TLR4 signaling and modulates innate immunity.