IL-4 enhances keratinocyte expression of CXCR3 agonistic chemokines

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-g lutamate-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-TAG 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-TAG mRNA accumulation in keratinocytes and increa sed the levels of IP-10 and Mig in keratinocyte supernatants, Immunohistoch emistry of skin affected by ACD revealed that >70% of infiltrating cells we re reactive for CXCR3 and that CXCR3 staining colocalized in CD4(+) and CD8 (+) T cells. Nickel-specific CD4(+) and CD8(+) T cell lines established fro m ACD skin produced IFN-gamma and IL-4 and expressed moderate to high level s of CXCR3, Finally, CXCR3 agonistic chemokines released by stimulated kera tinocytes triggered calcium mobilization in skin-derived nickel-specific CD 4(+) T cells and promoted their migration, with supernatant from keratinocy te cultures stimulated with IFN-gamma and IL-4 attracting more efficaciousl y than supernatant from keratinocytes activated with IFN-gamma alone. In co nclusion, IL-4 exerts a proinflammatory function on keratinocytes by potent iating IFN-gamma and TNF-alpha induction of IP-10, Mig, and I-TAG, which in turn may determine a prominent recruitment of CXCR3(+) T lymphocytes at in flammatory reaction sites.