Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes.
Keratinocytes are influenced by cytokines released by skin-infiltrating T lymphocytes. IL-17 is produced by activated CD4+ T cells and can stimulate epithelial cells. We investigated whether IL-17 could modulate the cytokine production and cell-surface molecule expression of keratinocytes. The effects of IL-17 were compared with those of IFN-gamma, which is also derived from activated T cells and is a strong stimulator for keratinocytes. IL-17 enhanced the mRNA and protein production of the proinflammatory cytokines IL-6 and IL-8 in a concentration-dependent way, and induced a weak expression of intercellular adhesion molecule (ICAM)-1 and HLA-DR. The production of IL-1alpha and IL-15 was not altered. IFN-gamma augmented the production of IL-6, IL-8, and IL-15 and strongly induced both cell-surface molecules. IL-17 and IFN-gamma showed marked synergism in the stimulation of IL-6 and IL-8 protein secretion and, to a lesser extent, in the induction of ICAM-1 and HLA-DR expression. The majority of the CD4+ and CD8+ T cell clones derived from lesional psoriatic skin expressed IL-17 mRNA, suggesting that skin-infiltrating T cells can produce this cytokine. This IL-17 mRNA expression was detectable in T helper cell type 1 and type 2 and did not correlate with the IFN-gamma or IL-4 production. In addition, IL-17 mRNA is detectable in biopsies from lesional psoriatic skin, but not in nonlesional control biopsies. Our study indicates that IL-17 is a proinflammatory cytokine, which could amplify the development of cutaneous inflammation and may support the maintenance of chronic dermatoses, through stimulation of keratinocytes to augment their secretion of proinflammatory cytokines.
Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands.
M B
MB
Teunissen
C W
CW
Koomen
R
R
de Waal Malefyt
E A
EA
Wierenga
J D
JD
Bos
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002999:Clone Cells / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004357:Drug Synergism; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics; D019409:Interleukin-15 / Q000235:genetics; D020381:Interleukin-17 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D015603:Keratinocytes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D008297:Male; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D006684:HLA-DR Antigens; D007375:Interleukin-1; D019409:Interleukin-15; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma