Histamine and TGF-beta, major mediators secreted by mast cells, are involved in skin inflammation and play critical roles in the pathogenesis of systemic sclerosis. However, the roles of signaling mechanisms in the development of skin fibrosis remain largely unclear. Here we show that histamine suppressed the expression of alpha smooth muscle actin (alpha SMA), a marker of myofibroblasts, induced by TGF-beta 1 in skin fibroblasts. Histamine Hi-receptor (H1R), but not H2-receptor (H2R) or H4-receptor (H4R), was expressed on skin fibroblasts at both mRNA and protein levels. Interestingly, an H1R antagonist, but not H2R or H4R antagonists, antagonized the histamine-mediated suppression of alpha SMA expression by TGF-beta 1. Correspondingly, phosphorylated Smad2 was detected after treatment with TGF-beta 1, whereas the addition of histamine inhibited this phosphorylation. Taken together, histamine-H1R decreased TGF-beta 1-mediated Smad2 phosphorylation and inhibited differentiation of skin fibroblasts into myofibroblasts. (C) 2015 Elsevier Inc. All rights reserved.