The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.The tandem zinc finger protein tristetraprolin (TTP; also known as Nup475, Tis11, or Zfp36) (23,26,40,46,62) is expressed in activated monocytic cells (13, 47) and T lymphocytes (49, 51). It functions to regulate the expression of tumor necrosis factor ␣ (TNF-␣) by binding to a conserved adenosine/uridine-rich element (ARE) within the 3Ј-untranslated region of TNF-␣ mRNA (13,31,32,36,47). TTP promotes both mRNA deadenylation and 3Ј to 5Ј degradation of the mRNA body (35, 37-39), consistent with its ability to recruit several factors involved in these processes (14,25,39,45). The pivotal role of TTP in the regulation of TNF-␣ is illustrated by the proinflammatory phenotype of a TTP Ϫ/Ϫ mouse strain, in which chronic overexpression of TNF-␣ by macrophages results in severe polyarthritis and cachexia (11,13,57). TTP has also been implicated in the posttranscriptional regulation of granulocyte-macrophage colony-stimulating factor (12), interleukin-2 (51), cyclooxygenase 2 (COX-2) (50), and inducible nitric oxide synthase (24). It may also regulate its own expression by binding to an ARE in the 3Ј untranslated region of TTP mRNA (60). The minimum binding site of TTP is the nonameric sequence UUAUUUAUU (2,3,38,65), and it is likely that additional posttranscriptional targets of TTP containing this sequence remain to be identified.The p38 mitogen-activated protein kinase (MAPK) and its downstream kinase MK2 play a central role in the posttranscriptional regulation of inflammatory gene expression in myeloid and other cells (5, 16, 20-22, 33, 34, 54). We and others have therefore investigated interactions of the p38 MAPK pathway with TTP. In a mouse macrophage-like...
There is increasing evidence that astrocytes play important roles in immune regulation in the brain. Astrocytes express toll-like receptors (TLR) and build up responses to innate immune triggers by releasing proinflammatory molecules. We investigate signaling pathways and released molecules after astrocyte TLR4 activation. Purified rodent brain astrocyte cultures were treated with the TLR4 activator bacterial lipopolysaccharide (LPS). Tools used to interfere with this system include small interference RNA, inhibitory drugs, and MyD88 or Stat1 deficient mice. LPS induced early activation of the transcription factor NFκB, through the MyD88 adaptor, and expression of TNF-α, VCAM-1, IL-15, and IL-27. LPS also induced delayed Jak1/Stat1 activation, which was MyD88-independent but was not mediated by IFN-β. Jak1/Stat1 activation induced the expression of negative cytokine regulator SOCS-1 and CXCL10 chemokine (IP-10). Mitogen-activated protein kinases (MAPK) were also involved in TLR4 signaling in a MyD88-independent fashion. p38 exerted a strong influence on LPS-induced gene expression by regulating the phosphorylation of Stat1 and the transcriptional activity of NFκB, while JNK regulated the Jak1/Stat1 pathway, and ERK1/2 controlled the expression of Egr-1 and influenced MyD88-dependent MMP-9 expression. Interplay between these signals was evidenced by the increased induction of MMP-9 in Stat1-deficient cells challenged with LPS, suggesting that Stat1 negatively regulates the expression of MMP-9 induced by LPS. Therefore, astrocytes are responsive to TLR4 activation by inducing a complex set of cell-dependent molecular reactions mediated by NFκB, MAPK and Jak1/Stat1 signaling pathways. Here we identified cross-talking signals generating a proinflammatory environment that will modulate the response of surrounding cells.
Background:The relative contribution of COX-2 and COX-1 to prostanoid formation under neuroinflammation is complex. Results: LPS induced COX-2 and mPGES1 but down-regulated COX-1 and TS in astroglia. These effects accounted for the high production of PGE 2 . Conclusion: PGE 2 after LPS results from the coordinated COX-2 up-regulation and COX-1 down-regulation in astrocytes. Significance: Changes in COX-2 and COX-1 expression mediate astroglial PGE 2 generation in neuroinflammation.
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