The production of pro-inflammatory cytokines and chemokines is increased during inflammatory bowel disease (IBD). Previously, it was demonstrated that brain derived neurotrophic factor (BDNF) expression is increased in experimental models of colitis. BDNF is partially responsible for the structural and functional changes that take place during IBD. However, the exact mechanisms underlying the upregulation of BDNF during gut inflammation are unknown. The aim of the present study was to determine the effects of direct treatment of smooth muscle cells with inflammatory cytokines on the synthesis and secretion of BDNF. BDNF expression and secretion levels were measured using ELISA kits on tissue lysates and on incubation media used to culture the rat colon smooth muscle tissues treated for 24 h with either tumor necrosis factor (TNF)-α or interleukin (IL)-1β. Compared with the control tissue samples, treatment with TNF-α and IL-1β resulted in a significant increase in the protein expression levels of BDNF in the incubated smooth muscle tissue. TNF-α and IL-1β also stimulated the secretion of BDNF. Chelation of intracellular Ca with BABTA-AM prevented the TNF-α and IL-1β-induced increase in BDNF protein expression and secretion levels. Furthermore, inhibition of protein kinase A (PKA) significantly reduced BDNF expression levels when treated with cytokines but not secretion. In conclusion, proinflammatory cytokines that are upregulated during IBD, directly stimulated BDNF expression and secretion in a Ca dependent manner. Considering the ability of BDNF to enhance smooth muscle contraction and pain sensation, this autocrine loop may partially explain the characteristic hypercontractility and hypersensitivity associated with IBD.