Molecular basis of the alpha-MSH/IL-1 antagonism.
The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) is recognized as a potent mediator of immune and inflammatory reactions. Accordingly, alpha-MSH in vitro, as well as in vivo, antagonizes the proinflammatory activities of cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF alpha). Since the molecular basis of these antiinflammatory effects is not well known, the influence of alpha-MSH on IL-1 beta-induced chemokine production and transcription factor activation was investigated in human keratinocytes. alpha-MSH, in a dose-dependent manner, after 48 h, significantly reduced the IL-1 beta mediated secretion of the C-X-C chemokines IL-8 and Gro alpha. This was confirmed by semiquantitative RT-PCR, which revealed a marked down-regulation in IL-8 and Gro alpha mRNA expression. Furthermore, we determined the effect of alpha-MSH on the IL-1 beta-induced activation of the nuclear factor kappa B (NF kappa B)--a major transcription factor for chemokine genes. Electrophoretic mobility-shift-assays showed that alpha-MSH, in a dose range from 10(-6) to 10(-12) M, significantly downregulated the IL-1 beta-induced activation of NF kappa B 10 minutes after stimulation. Therefore, NF kappa B inactivation by alpha-MSH appears to be a crucial event, one that is responsible for the downregulation of cytokine gene transcription.
Brzoska
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Ludwig Boltzmann Institute of Cellbiology and Immunobiology of the Skin, Department of Dermatology, University Muenster, Germany.
Kalden
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Scholzen
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Luger
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D002460:Cell Line; D054360:Chemokine CXCL1; D018925:Chemokines / Q000235:genetics*; D019743:Chemokines, CXC / Q000235:genetics; D002630:Chemotactic Factors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*; D016209:Interleukin-8 / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*; D000521:alpha-MSH / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D014157:Transcription Factors; D000521:alpha-MSH