Interleukin (IL)-4 and transforming growth factor (TGF)-β1 have been implicated in the pathogenesis of asthma and fibrosis, respectively. We hypothesized that IL-4 and TGF-β1 have a synergetic effect in the formation of subepithelial or peribronchial fibrosis in asthma following chronic inflammation. To demonstrate this, human fetal lung fibroblasts were cultured in native type I collagen gels. Both contraction in the presence or absence of IL-4 and/or TGF-β1, and the effect of IL-4 and/or TGF-β1 on native type I collagen degradation, induced by IL-1β and tumor necrosis factor (TNF)-α plus trypsin, was determined. Both IL-4 (1 to 10 ng/mL) and TGF-β1 (10 to 100 pmol/L) were able to augment collagen gel contraction in a concentration-dependent manner. TGF-β1 effect was more potent than IL-4 within 48 h after release of the gels (TGF-β, 57.48 ± 1.40% and IL-4, 70.26 ± 0.32%, respectively, vs 76.95 ± 0.99% of control on day 1). After 2 days, however, the potency of TGF-β1 was dramatically decreased, while the IL-4 effect was more potent after 3 days (TGF-β1, 50.50 ± 0.11% and IL-4, 26.97 ± 0.38% vs 46 ± 1.54% of control on day 5). When IL-4 and TGF-β1 were added together, further augmentation was observed at all times (47.31 ± 0.88% on day 1 and 22.89 ± 0.85% on day 5). In addition, IL-4 and/or TGF-β1 significantly inhibited collagen gel degradation induced by IL-1β and TNF-α plus trypsin (hydroxyproline in the remaining gels: IL-1β plus TNF-α, 21.0 ± 1.3; IL-1β plus TNF-α plus IL-4, 35.3 ± 1.4; IL-1β plus TNF-α plus TGF-β1, 55.6 ± 1.7; IL-1β plus TNF-α plus IL-4 plus TGF-β1, 69.6 ± 1.8 vs 97.3 ± 2.9 μg per gel of control). Consistently, IL-4 and/or TGF-β1 stimulated tissue inhibitor of metalloproteinase-1 production (control, 180.8 ± 6.44; IL-4, 316.1 ± 19.79; TGF-β1, 550.2 ± 15.6; IL-4 plus TGF-β1, 865.3 ± 25.3 ng/mL). Furthermore, IL-4 and/or TGF-β1 had no effect on matrix metalloproteinase (MMP)-1 production but significantly blocked the trypsin-mediated conversion of pro–MMP-1 into an active form of MMP-1. These data suggest that IL-4 and TGF-β1 have a collaborative effect in augmenting fibroblast-mediated extracellular matrix contraction and can inhibit extracellular matrix degradation mediated by metalloproteinases. Thus, IL-4 and TGF-β1 may play an important role in fibroblast-mediated tissue remodeling and fibrosis.