Key result
Interleukin-13 synergistically augmented transforming growth factor-beta1-induced TIMP-1 mRNA and protein expression in primary human airway fibroblasts (P<0.001 vs. TGF-beta1 alone).
Why the study?
Does IL-13 augment TGF-beta1-induced TIMP-1 expression in primary human airway fibroblasts?
Does IL-13 augment TGF-beta1-induced TIMP-1 expression in primary human airway fibroblasts?
p-value: p=<0.001
IL-13 synergistically augments TGF-beta1-induced profibrotic responses (TIMP-1 expression) in human airway fibroblasts, though the PI3K-Akt pathway may negatively regulate this production.
May inform profibrotic mechanisms in airway disease; leaves open whether IL-13/TGF-β1 synergy warrants targeted therapies.
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-beta1 (TGF-beta1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF-beta. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF-beta1 (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-beta1-induced TIMP-1 mRNA and protein expression (P < 0.001 vs. TGF-beta1 alone). The upregulation of TIMP-1 by the combination of TGF-beta1 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-beta1, 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-beta1-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-beta1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.
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Zhou et al. (2004) studied this question. Interleukin-13 combined with TGF-beta1 vs. TGF-beta1 alone was evaluated on TIMP-1 mRNA and protein expression (p=<0.001). Interleukin-13 synergistically augmented transforming growth factor-beta1-induced TIMP-1 mRNA and protein expression in primary human airway fibroblasts (P<0.001 vs. TGF-beta1 alone).
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