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Objective was to elucidate the role of NE in fibrosis in SSc. IL-6 is a potent stimulator of collagen production in fibroblasts. NE enhanced IL-6 production and proliferation more significantly in SSc fibroblasts than in normal fibroblasts. Furthermore, the production of IL-6 and phosphorylation of p38 in SSc fibroblasts was enhanced by adrenergic receptor (AR)\u03b2 agonist, isoproterenol, but not AR\u03b1 agonist, oxymetazoline. AR\u03b2 blocker, propranolol, inhibited NE-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. NE-induced IL-6 was significantly inhibited by p38 inhibitor, SB203580, suggesting that NE-induced phosphorylation of p38 via AR\u03b2 enhances IL-6 production in SSc fibroblasts. NE-induced phosphorylation of ERK1\/2 via AR\u03b1 inhibited IL-6 production in SSc fibroblasts. Combined treatment with NE and endothelin-1 resulted in an additive increase in IL-6 production in SSc fibroblasts. NE-induced IL-6\/IL-6 receptor trans-signaling increased the production of collagen type I in SSc fibroblasts and both propranolol and SB203580 inhibited NE-induced collagen production. 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