Decorin Affects Cytokine Expression

The proteoglycan decorin modulates leukocyte recruitment during delayed-type hypersensitivity (DTH) responses. Decorindeficient (Dcn) mice show reduced edema formation during the first 24 h with a concurrent attenuated recruitment of Cd8 leukocytes in the inflamed Dcn ears. The aim of this study was to elucidate the molecular pathways affected by the loss of decorin. In vivo, reduced numbers of Cd8 cells in Dcn ears correlated with a reduced interferon-γ (Ifn-γ) and CXCL-10 expression. In vitro, Dcn lymphocytes displayed an increased adhesion to brain microvascular (bEnd.3) endothelial cells. Decorin treatment of bEnd.3 increased Icam-I and downregulated Vcam-I expression after Tnf-α stimulation. However, Dcn and wild-type lymphocytes produced Ifn-γ after activation with Cd3ε. Upon incubation with decorin, endothelial cells and fibroblasts responded differently to Ifn-γ and Tnf-α: Ccl2 in bEnd.3 cells was more prominently up-regulated by Tnf-α compared to Ifn-γ. Notably, both factors were more potent in the presence of decorin. Compared to Tnf-α, Ifn-γ treatment induced significantly more CXCL-10, and both factors increased synthesis of CXCL-10 in the presence of decorin. The response to Ifn-γ was similar in Dcn and wild-type fibroblasts, an additional source of CXCL-10. However, addition of decorin yielded significantly more CXCL-10. Notably, decorin increased the stability of Ifn-γ in vitro, and potentiated Ifn-γ-induced activation of Stat-1. Furthermore, only dermatan sulfate influenced Ifn-γ signaling by significantly increasing CXCL-10 expression in contrast to decorin protein core alone. Our data demonstrate that decorin modulates DTH responses by augmenting the http://www.jbc.org/cgi/doi/10.1074/jbc.M112.419366 The latest version is at JBC Papers in Press. Published on March 4, 2013 as Manuscript M112.419366