Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases.
Interleukin (IL)-18 has been described to play a role in several inflammatory skin diseases such as eczema and psoriasis. In this study, we aimed to elucidate keratinocytes as potential targets for IL-18 effects. In human primary keratinocytes expression of IL-18Ralpha as well as responses to IL-18 were determined. In keratinocytes freshly isolated from skin biopsies of lesional atopic dermatitis or psoriasis, we observed a significantly higher expression of the IL-18Ralpha as compared with keratinocytes from normal donors. A marked upregulation was induced in vitro upon stimulation with interferon (IFN)gamma+tumor necrosis factor (TNF)alpha or poly I:C. IL-4 led to downregulation of IL-18Ralpha. IL-18-induced CXCL10/IP-10 production in freshly isolated keratinocytes from lesional psoriasis as well as in cultured normal keratinocytes. Furthermore, IL-18 upregulated major histocompatibility complex (MHC) class II expression on IFNgamma-stimulated keratinocytes. This was of functional significance as verified in coculture experiments with CD4+ T cells in the presence of superantigen. T cells produced significant amounts of IFNgamma after coculture with IL-18-induced MHC class II expressing keratinocytes. In conclusion, we have shown that keratinocytes functionally respond to IL-18 with upregulation of MHC II and production of the chemokine CXCL10/IP-10. These findings further support an important role of IL-18 in inflammatory skin diseases in the epidermal compartment.
Wittmann
Miriam
M
Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany. wittman.mariam@mh-hannover.de
Purwar
Rahul
R
Hartmann
Christina
C
Gutzmer
Ralf
R
Werfel
Thomas
T
D015496:CD4-Positive T-Lymphocytes; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis; D002908:Chronic Disease; D018920:Coculture Techniques; D003872:Dermatitis / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D015847:Interleukin-4 / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000187:drug effects; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology; D018123:Receptors, Interleukin / Q000378:metabolism; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D016328:NF-kappa B; D020033:Protein Isoforms; D011506:Proteins; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4