The Mitogen-activated Protein (MAP) Kinase p38 and Its Upstream Activator MAP Kinase Kinase 6 Are Involved in the Activation of Signal Transducer and Activator of Transcription by Hyperosmolarity

Bode, Johannes G.; Gatsios, Petros; Ludwig, Stephan; Rapp, Ulf R.; Häussinger, Dieter; Heinrich, Peter C.; Graeve, Lutz

doi:10.1074/jbc.274.42.30222

Cited by 102 publications

(75 citation statements)

References 36 publications

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Section: Figuresupporting

confidence: 57%

“…When cells are treated with high concentrations of sorbitol, stress kinases can contribute to Stat activation (68,69). Sorbitol (600 mM) was required for effective Stat activation, which was independent of gp130 or Jaks, but seemed to depend upon cell shrinkage (68,69).…”

Section: Figurementioning

confidence: 99%

“…Sorbitol (600 mM) was required for effective Stat activation, which was independent of gp130 or Jaks, but seemed to depend upon cell shrinkage (68,69). We did not detect Stat activation when 400 mM sorbitol was used, possibly secondary to low levels of Stat activation at this concentration, as previously reported (68,69). Our results are consistent with the experience from a large number of laboratories that physiologic activators of stress kinases, such as IL-1 and TNF, do not typically activate Stat tyrosine phosphorylation or DNA binding (70).…”

Section: Figurementioning

confidence: 99%

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Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Ahmed¹,

Ivashkiv

2000

The Journal of Immunology

120

110

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The development and resolution of an inflammatory process are regulated by a complex interplay among cytokines that have pro- and anti-inflammatory effects. Effective and sustained action of a proinflammatory cytokine depends on synergy with other inflammatory cytokines and antagonism of opposing cytokines that are often highly expressed at inflammatory sites. We analyzed the effects of the inflammatory and stress agents, IL-1, TNF-α, LPS, sorbitol, and H2O2, on signaling by IL-6 and IL-10, pleiotropic cytokines that activate the Jak-Stat signaling pathway and have both pro- and anti-inflammatory actions. IL-1, TNF-α, and LPS blocked the activation of Stat DNA binding and tyrosine phosphorylation by IL-6 and IL-10, but not by IFN-γ, in primary macrophages. Inhibition of Stat activation correlated with inhibition of expression of IL-6-inducible genes. The inhibition was rapid and independent of de novo gene induction and occurred when the expression of suppressor of cytokine synthesis-3 was blocked. Inhibition of IL-6 signaling was mediated by the p38 subfamily of stress-activated protein kinases. Jak1 was inhibited at the level of tyrosine phosphorylation, indicating that inhibition occurred at least in part upstream of Stats in the Jak-Stat pathway. Experiments using Stat3 mutated at serine 727 and using truncated IL-6Rs suggested that the target of inhibition is contained within the membrane-proximal region of the cytoplasmic domain of the gp130 subunit of the IL-6 receptor and is different from the SH2 domain-containing protein-tyrosine phosphatase/suppressor of cytokine synthesis-3 docking site. These results identify a new level at which IL-1 and TNF-α modulate signaling by pleiotropic cytokines such as IL-6 and IL-10 and provide a molecular basis for the previously described antagonism of certain IL-6 actions by IL-1.

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Section: Figuresupporting

confidence: 57%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Ahmed¹,

Ivashkiv

2000

The Journal of Immunology

120

110

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“…27 Although most reports link MAPKs to nuclear signaling, it seems clear that all of them phosphorylate both nuclear and cytoplasmic targets. The JNKs and p38s are activated by most environmental stresses (hence the name SAPKs for Stress Activated Protein Kinases) such as hyperosmolarity 28,29 and some of them can also be activated by cytokines and TNF-a. 9,26 ± 30 All these kinases play critical roles as components of the signal transduction pathways that control cell differentiation, the cell cycle, and cell death.…”

Section: Introductionmentioning

confidence: 99%

Osmotic stress sensitizes naturally resistant cells to TNF-α-induced apoptosis

et al. 2002

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Most cells are naturally resistant to TNF-a-induced cell death and become sensitized when NF-kB transactivation is blocked or in the presence of protein synthesis inhibitors that prevent the expression of anti-apoptotic genes. In this report we analyzed the role of osmotic stress on TNF-a-induced cell death. We found that it sensitizes the naturally resistant HeLa cells to TNF-a-induced apoptosis, with the involvement of an increase in the activity of several kinases, the inhibition of Bcl-2 expression, and a late increase on NF-kB activation. Cell death occurs regardless of the enhanced NF-kB activity, whose inhibition produces an increase in apoptosis. The inhibition of p38 kinase, also involved in NF-kB activation, significantly increases the effect of osmotic stress on TNF-a-induced cell death.

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“…In addition to tyrosine phosphorylation, the serine phosphorylation of Stat molecules is also necessary for the maximal activation of transcription (13,14). Several lines of evidence suggest the role of different Ser/Thr kinases in serine phosphorylation of Stat molecules and their transactivation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Our recent studies demonstrated that p38 MAPK regulates serine 727 phosphorylation on Stat1 and Stat3 and that p38 MAPK activity is required for IL-13-induced 15-LO expression (27).…”

mentioning

confidence: 99%

Role of Protein Kinase C Isoforms in the Regulation of Interleukin-13-induced 15-Lipoxygenase Gene Expression in Human Monocytes

Bhattacharjee

Roy

et al. 2004

Journal of Biological Chemistry

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We reported previously that interleukin-13 (IL-13) induces tyrosine phosphorylation/activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6 in primary human monocytes. We recently revealed that p38 MAPK-mediated serine phosphorylation of both Stat1 and Stat3 is required for the induction of 15-lipoxygenase (15-LO) expression by IL-13. In this study, we present data indicating that another serine/threonine kinase, PKC␦, is also required for IL-13-induced 15-LO expression. PKC␦, a member of the novel protein kinase C (PKC) subclass, was rapidly phosphorylated and activated upon exposure to IL-13. Treatment of cells with rottlerin, a PKC␦ inhibitor, blocked IL-13-induced 15-LO mRNA and protein expression, whereas Go6976, an inhibitor of the conventional PKC subclass, had no inhibitory effects. Down-regulation of cellular PKC␦ protein levels by PKC␦-specific antisense oligodeoxyribonucleotides also inhibited 15-LO expression markedly. IL-13-induced 15-LO expression resulted in significant inhibition of synthesis of the potent chemotactic factor leukotriene B 4 , and that process was reversed by rottlerin, presumably through the blockage of PKC␦-dependent 15-LO expression. Furthermore, our data demonstrate that IL-13-mediated activation of PKC␦ and p38 MAPK are independent pathways, because inhibition of one kinase activity had no effect on the other, suggesting that the two pathways act in parallel to regulate the downstream targets necessary for 15-LO expression. Inhibition of PKC␦ activation by rottlerin also markedly attenuated IL-13-induced Stat3 DNA binding activity. Our findings indicate that PKC␦ plays an important role in regulating IL-13-induced 15-LO expression in human monocytes and subsequently modulates the inflammatory responses mediated by 15-LO products.Th2 lymphocytes secrete IL-4 1 and IL-13, which have the unique ability to induce the expression of the lipid-oxidizing enzyme 15-LO in primary human monocytes (1-3). To date, no monocytic cell lines have been shown to respond in a similar fashion. 15-LO dioxygenates polyenoic fatty acids to their corresponding hydroperoxide derivatives. These molecules are potent mediators of inflammatory responses and are found in atherosclerotic lesions. It is believed that 15-LO products play an important role in the pathogenesis of atherosclerosis and other inflammatory diseases (4 -7). In addition to its pro-inflammatory actions, 15-LO has also been shown to suppress the inflammatory responses by inhibiting the production of the potent chemotactic factor LTB 4 . This process has been observed in several cell types, including human monocytes (8 -10).Previously, we demonstrated that Jak2 and Tyk2 are upstream tyrosine kinases involved in regulating IL-13-induced expression of 15-LO (3). We have further defined the functional IL-13 receptor complex, the association of Jaks with the receptor constituents, and the tyrosine phosphorylation and activation of Stats in response to IL-13 (11). Tyrosine phosphorylation of Stat molecules facilitates the formation of di...

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The Mitogen-activated Protein (MAP) Kinase p38 and Its Upstream Activator MAP Kinase Kinase 6 Are Involved in the Activation of Signal Transducer and Activator of Transcription by Hyperosmolarity

Cited by 102 publications

References 36 publications

Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Osmotic stress sensitizes naturally resistant cells to TNF-α-induced apoptosis

Role of Protein Kinase C Isoforms in the Regulation of Interleukin-13-induced 15-Lipoxygenase Gene Expression in Human Monocytes

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