Systematic Evaluation of the Mitogen-Activated Protein Kinases in the Induction of iNOS by Tumor Necrosis Factor-Alpha and Interferon-Gamma (original) (raw)
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Mitogen-activated Protein Kinases in Inflammation
Mitogen-activated protein kinases (MAPKs) play critical regulatory roles in the production of the pro-inflammatory cytokines and downstream signaling events which lead to inflammation. Inflammation is a primarily localized and protective response of host against microbial infection. C ontrolled inflammation is beneficial and necessary for host defense while uncontrolled inflammatory response results in inflammatory diseases such as septic shock, rheumatoid arthritis and cancer. The MAPK family consists of three subfamilies; the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and the p38 MAPKs. MA PKs are involved in transmitting extracellular signals to nucleus which leads to gene regulation. In this review, we summarize the current knowledge of ERK1/2, JNKs, and p38 MAPK members and their roles in inflammation.
American Journal of Physiology-Cell Physiology, 2001
Nitric oxide (NO·) produced by inducible nitric oxide synthase (iNOS) mediates a number of important physiological and pathophysiological processes. The objective of this investigation was to examine the role of mitogen-activated protein kinases (MAPKs) in the regulation of iNOS and NO· by interferon-γ (IFN-γ) + lipopolysaccharide (LPS) in macrophages using specific inhibitors and dominant inhibitory mutant proteins of the MAPK pathways. The signaling pathway utilized by IFN-γ in iNOS induction is well elucidated. To study signaling pathways that are restricted to the LPS-signaling arm, we used a subclone of the parental RAW 264.7 cell line that is unresponsive to IFN-γ alone with respect to iNOS induction. In this RAW 264.7γNO(−) subclone, IFN-γ and LPS are nevertheless required for synergistic activation of the iNOS promoter. We found that extracellular signal-regulated kinase (ERK) augmented and p38mapkinhibited IFN-γ + LPS induction of iNOS. Dominant-negative MAPK kinase-4 inhib...
The Journal of Immunology
The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-γ and a number of stimuli, including TNF-α. Recent work has shown that TNF-α activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-γ and TNF-α. All three kinases were activated during costimulation with IFN-γ and TNF-α. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition,...
Regulation of TNF Expression by Multiple Mitogen-Activated Protein Kinase Pathways
The Journal of …, 2000
Stimulating macrophages with bacterial endotoxin (LPS) activates numerous intracellular signaling pathways that lead to the production of TNF. In this study, we show that four mitogen-activated protein (MAP) kinase pathways are activated in LPSstimulated macrophages: the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase, p38, and Big MAP kinase (BMK)/ERK5 pathways. Although specific activation of a single MAP kinase pathway produces only a modest effect on TNF promoter activation, activation of each MAP kinase pathway is important for full induction of the TNF gene. Interestingly, a dramatic induction of TNF promoter-driven gene expression was observed when all of the four MAP kinase pathways were activated simultaneously, suggesting a cooperative effect among these kinases. Unexpectedly, cis elements known to be targeted by MAP kinases do not play a major role in multiple MAP kinase-induced TNF gene expression. Rather, a 40-bp sequence harboring the TATA box, is responsible for the gene up-regulation induced by MAP kinases. The proximity of the MAP kinase-responsive element to the transcriptional initiation site suggested that MAP kinases regulate the transcriptional initiation complex.
Modulation of Tumor Necrosis Factor and Interleukin-1-dependent NF-kappa B Activity by mPLK/IRAK
Journal of Biological Chemistry, 1999
The innate immune response is an important defense against pathogenic agents. A component of this response is the NF-B-dependent activation of genes encoding inflammatory cytokines such as interleukin-8 (IL-8) and cell adhesion molecules like E-selectin. Members of the serine/threonine innate immune kinase family of proteins have been proposed to mediate the innate immune response. One serine/threonine innate immune kinase family member, the mouse Pelle-like kinase/human interleukin-1 receptor-associated kinase (mPLK/ IRAK), has been proposed to play an obligate role in promoting IL-1-mediated inflammation. However, it is currently unknown whether mPLK/IRAK catalytic activity is required for IL-1-dependent NF-B activation. The present study demonstrates that mPLK/IRAK catalytic activity is not required for IL-1-mediated activation of an NF-B-dependent signal. Intriguingly, catalytically inactive mPLK/IRAK inhibits type 1 tumor necrosis factor (TNF) receptor-dependent NF-B activation. The pathway through which mPLK/IRAK mediates this TNF response is TRADD-and TRAF2-independent. Our data suggest that in addition to its role in IL-1 signaling, mPLK/IRAK is a component of a novel signal transduction pathway through which TNF R1 activates NF-B-dependent gene expression.
Cellular Signalling, 2003
The many specific, yet overlapping and redundant activities of individual cytokines have been the basis for current concepts of therapeutical intervention. Cytokines are powerful two-edged weapons that can trigger a cascade of reactions and may show activities that often go beyond the single highly specific property that it is hoped they possess. Nevertheless, it can be stated that our new, though burgeoning, understanding of the biological mechanisms governing cytokine actions is an important contribution to medical knowledge. The crucial role of the anti-inflammatory cytokine, interleukin (IL)-10, in regulating potential molecular pathway mediating injury and cell death has attracted paramount attention in recent years. In this respect, the mitogen-activated protein kinase (MAPK) components have emerged as potential signalling cascades that regulate a plethora of cell functions, including inflammation and cell death. The biochemistry and molecular biology of cytokine actions, particularly IL-10, explain some well known and sometimes also some of the more obscure clinical aspects of the evolution of diseases.
Molecular Immunology, 2009
a b s t r a c t IRAK-1 and IRAK-4 are protein kinases that mediate signaling by Toll/IL1/Plant R (TIR) domain-containing receptors including the IL-1, IL-18, and Toll-like receptors (TLRs). Although well studied in mouse systems, the mechanism by which they function in human systems is less clear. To extend our knowledge of how these proteins regulate inflammatory signaling in human cells, we genetically and pharmacologically manipulated IRAK-1 and IRAK-4 kinase activities in vitro. Ablation of IRAK-4 expression in human umbilical vein endothelial cells (HUVEC) with siRNA suppressed IL-1 induced IL-6 and IL-8 production whereas IRAK-1 siRNA suppressed TNF␣ induced but not IL-1 induced cytokine production. Complementation of IRAK-4-depleted cells with a kinase-inactive allele restored IL-1 induced cytokine gene expression suggesting that the IRAK-4 kinase activity is dispensable relative to its scaffolding function. Consistent with this finding, an IRAK-4 selective kinase inhibitor (RO6245) that inhibited IRAK-1 degradation failed to block IL-1 induced cytokine production. In contrast, an inhibitor of both IRAK-1 and IRAK-4 (RO0884) reduced IL-1 induced p38 MAP kinase, c-Jun N-terminal kinase activation, and IL-6 production in HUVEC. RO0884 also antagonized IL-1, TNF␣, and TLR-mediated cytokine production in human fibroblast-like synoviocytes and peripheral blood mononuclear cells. Therefore in human cells the nonkinase functions of IRAK-4 are essential, whereas the kinase activity of IRAK-4 appears redundant with that of IRAK-1. Pharmacologic inhibition of both kinases appears necessary to block pro-inflammatory cytokine production.