Interleukin-1 Receptors and their Ligands

Detta är en avhandling från Stockholm : Stockholm University

Sammanfattning: Interleukin-1 (IL-1) is an endogenous mediator of the inflammatory response. IL-1 executes its actions by binding and subsequent activation of the IL-1 receptor (IL-1R) proteins. Among the many systemic effects of IL-1, the fever response was the first to be investigated.We characterised, by cDNA sequence analysis, the primary structure of the type II IL-1 receptor (IL-1RII) expressed in the rat insulinomab-cell line Rinm5F. In addition, we found that IL-1R agonists upregulated the mRNA concentrations of IL-1RI and IL-1RII in Rinm5F cells.By generation of IL-1R subtype selective mutants of human IL-1bwe created pharmacological tools to investigate IL-1R subtype specific signalling in vivo. We showed that the type I IL-1R (IL-1RI) mediates the induction of fever, activation of the hypothalamic-pituitary-adrenal axis and induction of IL-6 expression by IL-1bin the rat.We presented data on an interaction between the IL-1RII and the IL-1 receptor accessory protein (IL-1RAcP) in the presence of IL-1b, suggesting a novel mechanism of regulating the cellular responsiveness to IL-1bi.e., by a competition between IL-1RII and the signalling IL-1RI for interaction with IL-1RAcP.We showed that mice deficient in IL-1bresponded with exacerbated fever when challenged with IL-1aorbor lipopolysaccharide (LPS) of E. coli, as compared to wild type mice. We found increased concentrations of IL-6 mRNA in the hypothalamus from untreated IL-1bdeficient mice as compared to wild type mice, suggesting the IL-1bdeficient mice to have compensated for the lack of IL-1bwith an increased expression of the functionally related pro-inflammatory cytokine IL-6.Using mice deficient in IL-1RAcP we showed that IL-1RAcP is involved in IL-1R signalling, as measured by lack of IL-1binduced NFkB activation and IL-1aorbinduced fever. In the same manner as mice deficient in IL-1b, the IL-1RAcP deficient mice responded with a fever when challenged with LPS suggesting that IL-1 is not essential for fever per se.

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