title: IL-4 enhances keratinocyte expression of CXCR3 agonistic chemokines.
abstract: IFN-induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC) belong to the non-glutamate-leucine-arginine motif CXC chemokine family and act solely through the CXCR3 receptor for potent attraction of T lymphocytes. In this study, we evaluated the capacity of the T cell-derived cytokines IL-4, IL-10, and IL-17 to modulate IP-10, Mig, and I-TAC in cultured human keratinocytes and CXCR3 expression in T cells from allergic contact dermatitis (ACD). IL-4, but not IL-10 or IL-17, significantly up-regulated IFN-gamma- or TNF-alpha-induced IP-10, Mig, and I-TAC mRNA accumulation in keratinocytes and increased the levels of IP-10 and Mig in keratinocyte supernatants. Immunohistochemistry of skin affected by ACD revealed that >70% of infiltrating cells were reactive for CXCR3 and that CXCR3 staining colocalized in CD4+ and CD8+ T cells. Nickel-specific CD4+ and CD8+ T cell lines established from ACD skin produced IFN-gamma and IL-4 and expressed moderate to high levels of CXCR3. Finally, CXCR3 agonistic chemokines released by stimulated keratinocytes triggered calcium mobilization in skin-derived nickel-specific CD4+ T cells and promoted their migration, with supernatant from keratinocyte cultures stimulated with IFN-gamma and IL-4 attracting more efficaciously than supernatant from keratinocytes activated with IFN-gamma alone. In conclusion, IL-4 exerts a proinflammatory function on keratinocytes by potentiating IFN-gamma and TNF-alpha induction of IP-10, Mig, and I-TAC, which in turn may determine a prominent recruitment of CXCR3+ T lymphocytes at inflammatory reaction sites.
authors.affiliation: Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy. c.albanesi@iti.it
authors.forename: C
authors.initials: C
authors.lastname: Albanesi
authors.forename: C
authors.initials: C
authors.lastname: Scarponi
authors.forename: S
authors.initials: S
authors.lastname: Sebastiani
authors.forename: A
authors.initials: A
authors.lastname: Cavani
authors.forename: M
authors.initials: M
authors.lastname: Federici
authors.forename: O
authors.initials: O
authors.lastname: De Pità
authors.forename: P
authors.initials: P
authors.lastname: Puddu
authors.forename: G
authors.initials: G
authors.lastname: Girolomoni
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D002474:Cell-Free System / Q000276:immunology; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism*; D009532:Nickel / Q000276:immunology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists* / Q000096:biosynthesis*; D012867:Skin / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D016753:Interleukin-10; D015847:Interleukin-4; D009532:Nickel; D007371:Interferon-gamma; D002118:Calcium