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.
Teunissen
M B
MB
Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands.
Koomen
C W
CW
de Waal Malefyt
R
R
Wierenga
E A
EA
Bos
J D
JD
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