Corticotropin-releasing factor receptor type 2beta, expressed in the rodent cardiovascular system, is a member of the G protein-coupled receptor family. This receptor is coupled positively to adenylate cyclase and is bound preferentially by the urocortin (Ucn)-related peptides (Uncs): Ucn, Ucn II, and Ucn III. In the present study, we investigated the effects of Ucns on IL-6 levels in A7r5 aortic smooth muscle cells. In this cell line, both Ucn and Ucn II induced accumulation of intracellular cAMP via corticotropin-releasing factor receptor type 2beta and also caused a significant increase in IL-6 output levels. The adenylate cyclase inhibitor, MDL-12330A, inhibited this Ucn- or Ucn II-induced increase in IL-6 levels. Although H89 (10 micro M), a protein kinase A inhibitor, had no effect on the increase in IL-6 concentration, bisindolylmaleimide I (10 nM), a protein kinase C inhibitor, was found to significantly inhibit IL-6 output levels. Blockade of Ucn- or Ucn II-induced increases in IL-6 levels by SB203580 (100 nM), a p38 MAPK inhibitor, suggested that the p38 MAPK pathway was involved in this regulation. The cAMP-mediated increase in IL-6 levels was suppressed synergistically by both bisindolylmaleimide I and SB203580. These findings demonstrate that both protein kinase C and p38 MAPK signaling cascades are involved downstream of the Ucns-cAMP pathway in A7r5 aortic smooth muscle cells.