Hsp27 regulates pro-inflammatory mediator release in keratinocytes by modulating NF-kappaB signaling.
Heat-shock protein 27 (Hsp27) is a member of the small Hsp family that functions as molecular chaperones and protects cells against environmental stress. Hsp27 is expressed in the upper epidermal layers of normal human skin and has been reported to play a role in keratinocyte differentiation and apoptosis. In this investigation, we show an additional role of Hsp27 in the regulation of inflammatory pathways in keratinocytes. Downregulation of Hsp27 using Hsp27-specific small interfering RNA increased prostaglandin E(2) (PGE(2)) production in both unstimulated and tumor necrosis factor-alpha (TNF-alpha)-stimulated keratinocytes. Moreover, downregulation of Hsp27 increased the release of the pro-inflammatory cytokine IL-8 from TNF-alpha-stimulated and UV-irradiated keratinocytes, and this increase was inhibited by pretreatment with the NF-kappaB inhibitor BAY11-7082. Further studies showed that downregulation of Hsp27 resulted in induction of NF-kappaB reporter activity in keratinocytes. This correlated with enhanced degradation of IkappaB-alpha protein and accumulation of phosphorylated IkappaB-alpha in Hsp27 knockdown cells. Moreover, Hsp27 associated with the IkappaB kinase (IKK) complex. As synthesis of the pro-inflammatory cytokine IL-8 and the prostanoid PGE(2) are regulated by NF-kappaB, this could be a probable mechanism by which Hsp27 modulates the production of these inflammatory cytokines. Thus, Hsp27 plays a protective role in regulating inflammatory responses in skin.
Sur
Runa
R
Preclinical Pharmacology, Johnson and Johnson Skin Research Center, CPPW, a Unit of Johnson & Johnson Consumer Companies Inc., Skillman, New Jersey 08558, USA.
Lyte
Peter A
PA
Southall
Michael D
MD
D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D018832:Molecular Chaperones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone