Interleukin-13 augments transforming growth factor- 1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts

Zhou, XiuXia, John B. Trudeau, Kathryn J. Schoonover, Jessica I. Lundin, Steve M. Barnes, Meghan J. Cundall, and Sally E. Wenzel. Interleukin-13 augments transforming growth factor1induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts. Am J Physiol Cell Physiol 288: C435– C442, 2005. First published September 29, 2004; doi:10.1152/ ajpcell.00035.2004.—Tissue inhibitor of metalloproteinase (TIMP)-1 is a potent inhibitor of activated matrix metalloproteinases (MMPs) such as gelatinases and collagenases. TIMP-1 is induced by transforming growth factor1 (TGF1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF1 (200 pM)-induced expression of TIMP-1 mRNA and protein in primary human airway fibroblasts obtained from 57 human subjects. IL-13 alone had no effect on TIMP-1 mRNA or protein expression. However, IL-13 synergistically augmented TGF1-induced TIMP-1 mRNA and protein expression (P 0.001 vs. TGF1 alone). The upregulation of TIMP-1 by the combination of TGF1 and IL-13 involved increased transcription, with little effect on mRNA stabilization. Initial exploration of the pathways leading to the synergy determined that activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway by IL-13 may have a negative effect on TIMP-1 production. The specific PI3K inhibitor LY-294002 in the presence of TGF1, IL-13, or the combination of the two caused significant increases in TIMP-1 mRNA expression, while LY-294002 increased TIMP-1 protein levels in the presence of IL-13 alone. These results suggest that IL-13 augments TGF1-induced profibrotic responses at both the mRNA and protein levels. Although IL-13 induced activation of PI3K-Akt, the activation did not contribute to the synergy observed with TGF1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.