Keratinocytes produce many cytochemokines that are involved in the pathogenesis of
skin disorders. In particular, the CC chemokines thymus and activation-regulated chemokine
(TARC)/macrophage-derived chemokine (MDC) play an important role in the infiltration
of Th2 cells. This study was undertaken to examine the regulatory effects of interleukin
(IL)-4, IL-13, and interferon (IFN)-gamma on TARC/MDC production in the human keratinocyte
cell line HaCaT. HaCaT cells spontaneously secrete TARC and MDC. The production of
TARC/MDC was downregulated by IL-4/IL-13, whereas it was upregulated by IFN-gamma.
To explore these regulatory mechanisms, we investigated the capacity of cytokines
to regulate expression of several adhesion molecules that may affect TARC/MDC production.
Of the adhesion molecules examined, the constitutive surface expression of E-cadherin
was downregulated by IL-4/IL-13, but was upregulated by IFN-gamma. Moreover, disruption
of the homophilic adherence of E-cadherin by anti-E-cadherin antibody or calcium chelation
abolished the production of TARC/MDC. We further examined the distribution of the
adherens junction complex composed of E-cadherin, alpha-catenin, beta-catenin, and
gamma-catenin. IL-4/IL-13 decreased the levels of membrane staining for adherens junction
proteins, whereas IFN-gamma increased membrane staining. Taken together, these results
suggest that IL-4/IL-13 and IFN-gamma induce alternations in the distribution of adherens
junctions in a different fashion and thereby contribute to the reciprocal regulation
of TARC/MDC production.