Abstract
In severe sepsis the host is overwhelmed partly by microorganisms and their products, and partly by inflammatory cytokines produced in response to the infection. The initial defense against microbial invasion, innate immunity, is mounted by mononuclear phagocytes which are scattered through most tissues. They have evolved receptors that detect microbial products. These have been called pattern recognition receptors and they detect unusual chemical structures not found in mammalian cells, such as lipopolysaccharides (LPS), lipoteichoic acid (LTA), peptidoglycans, muramyl peptides, mannans, unmethylated CpG motifs in bacterial DNA and so on [1]. The best known is CD14, which binds LPS, and probably other bacterial products. How the microbial substances signal to the interior of the cell has become clearer with the discovery of the Toll-like receptors (TLR) [2–4]. These are transmembrane proteins related to the interleukin (IL)-l receptor. The Toll prototype is found in Drosophila where it plays roles in development and protection against fungi. In mammals TLRs are activated by bacterial molecules (e.g., LPS bound to CD14), and signal by apparently the same pathways as IL-1. The molecule that mediates LPS and LTA signaling is TLR4, while TLR2 is involved in recognition of peptidoglycan of Gram-positive organisms. To what extent TLRs themselves bind microbial products is not yet clear; in the case of LPS the activation of TLR4 is indirect, the ligand for the TLR is not known. A very recent discovery is that TLR9 signals recognition of bacterial DNA [5]. The ligands and functions of the other TLRs are being searched for by many laboratories.
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References
Medzhitov R, Janeway CA (1997) Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 9:4–9
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397
Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (1998) A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95:588–593
Anderson KV (2000) Toll signaling pathways in the innate immune response. Curr Opin Immunol 12:13–19
Hemmi H, Takeuchi O, Kawai T, et al (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745
Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A (1998) The human Toll signaling pathway: divergence of nuclear factor kappa B and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med 187:2097–2101
Medzhitov R, Preston-Hurlburt P, Kopp E, et al (1998) MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2:253–258
Karin M (1999) The beginning of the end: IkappaB kinase (IKK) and NF-kappa B activation. J Biol Chem 274:27339–27342
Mercurio F, Manning AM (1999) Multiple signals converging on NF-kappaB. Curr Opin Cell Biol 11:226–232
Ip YT, Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development. Curr Opin Cell Biol 10:205–219
Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218
Matzinger P (1998) An innate sense of danger. Semin Immunol 10:399–415
Karin M, Liu Z, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9:240–246
Lekstrom-Himes J, Xanthopoulos KG (1998) Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 273:28545–28548
Galanis A, Yang SH, Sharrocks AD (2001) Selective targeting of MAPKs to the ETS domain transcription factor SAP-1. J Biol Chem 276:965–973
Yang SH, Whitmarsh AJ, Davis RJ, Sharrocks AD (1998) Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. Embo J 17:1740–1749.
Price MA, Rogers AE, Treisman R (1995) Comparative analysis of the ternary complex factors Elk-1, SAP-la and SAP-2 (ERP/NET). Embo J 14:2589–2601
Janknecht R, Hunter T (1997) Convergence of MAP kinase pathways on the ternary complex factor Sap-la. Embo J 16:1620–1627
Ridley SH, Dean JL, Sarsfield SJ, Brook M, Clark AR, Saklatvala J (1998) A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Lett 439:75–80
Dean JLE, Brook M, Clark AR, Saklatvala J (1999) p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem 274:264–269
Hazzalin CA, Cano E, Cuenda A, Barratt MJ, Cohen P, Mahadevan LC (1996) p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient. Curr Biol 6:1028–1031
Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 386:296–299
Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ (1996) FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. Embo J 15:4629–4642
Heidenreich O, Neininger A, Schratt G, et al (1999) MAPKAP kinase 2 phosphorylates serum response factor in vitro and in vivo. J Biol Chem 274:14434–14443
Young P, McDonnell P, Dunnington D, Hand A, Laydon J, Lee J (1993) Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents Actions C67–C69
Prichett W, Hand A, Sheilds J, Dunnington D (1995) Mechanism of action of bicyclic imidazoles defines a translational regulatory pathway for tumor necrosis factor alpha. J Inflamm 45:97–105
Ridley SH, Sarsfield SJ, Lee JC, et al (1997) Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 158:3165–3173
Brook M, Sully G, Clark AR, Saklatvala J (2000) Regulation of tumor necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. FEBS Lett 483:57–61
Kotlyarov A, Neininger A, Schubert C, et al (1999) MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol 1:94–97
Lasa M, Mahtani KR, Finch A, Brewer G, Saklatvala J, Clark AR (2000) Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol Cell Biol 20:4265–4274
Freshney NW, Rawlinson L, Guesdon F, et al (1994) Interleukin-1 activates a novel protein kinase cascade that results in phosphorylation of Hsp27. Cell 78:1039–1049
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387–398
Winzen R, Kracht M, Ritter B, et al (1999) The p38 MAP kinase pathway signals for cytokineinduced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. Embo J 18:4969–4980
Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J (2001) The 3’ untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 21:721–730
Keyse SM (2000) Protein phosphatases and the regulation of mitogen-activated protein kinase signaling. Curr Opin Cell Biol 12:186–192
Beutler B, Milsark IW, Cerami AC (1985) Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229:869–871
Newton R (2000) Molecular mechanisms of glucocorticoid action: what is important? Thorax 55:603–613
Ito K, Barnes PJ, Adcock IM (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-lbeta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 20:6891–6903
Gonzalez MV, Gonzalez-Sancho JM, Caelles C, Munoz A, Jimenez B (1999) Hormone-activated nuclear receptors inhibit the stimulation of the JNK and ERK signaling pathways in endothelial cells. FEBS Lett 459:272–276
Lasa M, Brook M, Saklatvala J, Clark AR (2001) Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol Cell Biol 21:771–780
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Saklatvala, J., Clark, A., Dean, J. (2002). The Intracellular Signaling Pathways of Inflammatory Stress. In: Evans, T.W., Fink, M.P. (eds) Mechanisms of Organ Dysfunction in Critical Illness. Update in Intensive Care and Emergency Medicine, vol 38. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56107-8_9
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DOI: https://doi.org/10.1007/978-3-642-56107-8_9
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