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RECEPTORS AND SIGNAL TRANSDUCTION

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

National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado

Submitted 20 January 2004 ; accepted in final form 21 September 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 factor-1 (TGF-1), 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 TGF-1 (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 TGF-1-induced TIMP-1 mRNA and protein expression (P < 0.001 vs. TGF-1 alone). The upregulation of TIMP-1 by the combination of TGF-1 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 TGF-1, 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 TGF-1-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 TGF-1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.

phosphatidylinositol 3-kinase; Akt; LY-294002

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