title: Interleukin-1 regulates keratinocyte expression of T cell targeting chemokines through interleukin-1 receptor associated kinase-1 (IRAK1) dependent and independent pathways.
abstract: IL-1 is a potent pro-inflammatory cytokine that activates intracellular signaling cascades some of which may involve IL-1 receptor associated kinase-1 (IRAK1). Psoriasis is a T cell dependent chronic inflammatory condition of the skin of unknown cause. IL-1 has been implicated in psoriasis pathology, but the mechanism has not been elucidated. Interestingly, expression of IRAK1 is elevated in psoriatic skin. To identify a potential link between IL-1, keratinocytes and T cells in skin inflammation we employed pathway-focused microarrays to evaluate IL-1 dependent gene expression in keratinocytes. Several candidate mRNAs encoding known T cell chemoattractants were identified in primary keratinocytes and the stable keratinocyte cell line HaCaT. CCL5 and CCL20 mRNA and protein levels were confirmed up-regulated by IL-1 in concentration and time-dependent manners. Furthermore IL-1 synergized with IFN-gamma and TNF-alpha. Expression of CXCL9, CXCL10 and CXCL11 mRNAs was also increased in response to IL-1, but protein could only be detected in medium from cells treated with IFN-gamma alone or in combination with IL-1. Over-expression of IRAK1 led to increased constitutive and cytokine induced production of CCL5 and CCL20. Inhibition of IRAK1 activity through RNAi or expression of a dominant negative mutant blocked production of CCL5 and CCL20 but had no effect upon the IL-1 enhancement of IFN-gamma induced CXCL9, CXCL10 and CXCL11 production. In conclusion IL-1 regulates T cell targeting chemokine production in keratinocytes through IRAK1 dependent and independent pathways. These pathways may contribute to acute and chronic skin inflammation.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, 89 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Sanmiguel
authors.forename: Florina
authors.initials: F
authors.lastname: Olaru
authors.forename: Jieliang
authors.initials: J
authors.lastname: Li
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mohr
authors.forename: Liselotte E
authors.initials: LE
authors.lastname: Jensen
mesh_terms: D002460:Cell Line; D019742:Chemokines, CC / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology*; D011565:Psoriasis / Q000276:immunology; D034622:RNA Interference; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D019742:Chemokines, CC; D019743:Chemokines, CXC; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D053592:Interleukin-1 Receptor-Associated Kinases