title: IL-17 expression in human herpetic stromal keratitis: modulatory effects on chemokine production by corneal fibroblasts.
abstract: Herpetic stromal keratitis (HSK) is an immunopathologic disease triggered by infection of the cornea with HSV. Key events in HSK involve the interaction between cornea-infiltrating inflammatory cells and resident cells. This interaction, in which macrophages, producing IL-1 and TNF-alpha, and IFN-gamma-producing Th1 cells play a crucial role, results in the local secretion of immune-modulatory factors and a major influx of neutrophils causing corneal lesions and blindness. The Th1-derived cytokine IL-17 has been shown to play an important role in several inflammatory diseases characterized by a massive infiltration of neutrophils into inflamed tissue. Here we show that IL-17 is expressed in corneas from patients with HSK and that the IL-17R is constitutively expressed by human corneal fibroblasts (HCF). IL-17 exhibited a strong synergistic effect with TNF-alpha on the induction of IL-6 and IL-8 secretion by cultured HCF. Secreted IL-8 in these cultures had a strong chemotactic effect on neutrophils. IL-17 also enhanced TNF-alpha- and IFN-gamma-induced secretion of macrophage-inflammatory proteins 1alpha and 3alpha, while inhibiting the induced secretion of RANTES. Furthermore, considerable levels of IFN-gamma-inducible protein 10 and matrix metalloproteinase 1 were measured in stimulated HCF cultures, while the constitutive secretion of monocyte chemotactic protein 1 remained unaffected. The data presented suggest that IL-17 may play an important role in the induction and/or perpetuation of the immunopathologic processes in human HSK by modulating the secretion of proinflammatory and neutrophil chemotactic factors by corneal resident fibroblasts.
authors.affiliation: Institute of Virology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Maertzdorf
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Georges M G M
authors.initials: GM
authors.lastname: Verjans
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000378:metabolism; D003315:Cornea / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004357:Drug Synergism; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism / Q000502:physiology; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins / Q000096:biosynthesis; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D018925:Chemokines; C109985:IL17RA protein, human; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D020781:Matrix Metalloproteinase 1