Matrix metalloproteinases (MMPs) degrade collagen, and mediate tissue remodeling. The novel cytokine interleukin (IL)-17 is expressed during various inflammatory conditions and modulates MMP expression. We investigated the effect of IL-17 on MMP1 expression in primary human cardiac fibroblasts (HCF), and delineated the signaling pathways involved. HCF were treated with recombinant human (rh) IL-17. MMP1 expression was analyzed by Northern blotting, RT-qPCR, Western blotting and ELISA; transcriptional induction and transcription factor (TF) binding by EMSA, ELISA and reporter assay; p38 MAPK and ERK1/2 activation by protein kinase assays and Western blotting. Signal transduction pathways were investigated using pharmacological inhibitors, siRNA, and adenoviral dominant negative (dn) expression vectors. IL-17 stimulated MMP1 gene transcription, net mRNA levels, protein and promoter reporter activity in HCF. This response was blocked by IL-17R/Fc chimera and IL-17R antibodies, but not by IL-6, TNF- or IL-1 antibodies. IL-17-stimulated type I collagenase activity was inhibited by MMP inhibitor GM6001 and by siRNA-mediated MMP1 knockdown. IL-17 stimulated AP-1 (c-Fos, c-Jun, Fra-1), NF-B (p50, p65) and C/EBP () DNA binding and reporter gene activities, effects attenuated by antisense oligonucleotides, siRNA-mediated knockdown, or expression of dominant negative signaling proteins. Inhibition of AP-1, NF-B or C/EBP activation attenuated IL-17-stimulated MMP1 expression. IL-17 induced p38 MAPK and ERK1/2 activation, and inhibition by SB203580 and PD98059 blunted IL-17-mediated TF activation and MMP1 expression. Our data indicate that IL-17 induces MMP1 in human cardiac fibroblasts directly via p38 MAPK- and ERK-dependent AP-1, NF-B and C/EBP activation, and suggest that IL-17 may play a critical role in myocardial remodeling.