Characterization of the Effect of Interleukin-10 on Silica-Induced Lung Fibrosis in Mice

Abstract

We previously described a reduction of silica-induced lung fibrosis in interleukin-10-deficient mice (IL-10-/-) (Huaux and colleagues; Am. J. Respir. Cell Mol. Biol. 1998;18:51-59). In the present study, we further dissect the exact functions of IL-10 in experimental silicosis. The reduced lung fibrotic response to silica in IL-10-/- mice was accompanied by a marked recruitment of TH1 CD4+ lymphocytes. However, treatment with anti-CD4 antibodies reduced silica-induced lung fibrosis in both IL-10-/- and IL-10+/+ mice, suggesting that this T cell population actually contributes to the extension of the fibrotic lesions in a manner that is independent of IL-10. In IL-10-/- mice, silica-induced lung production of the profibrotic mediator transforming growth factor (TGF)-beta1 and the antifibrotic eicosanoid PGE2 were reduced and increased, respectively, relative to that in IL-10+/+ mice. In addition, in vitro experiments indicated that recombinant IL-10 upregulated TGF-beta1 expression in alveolar macrophages while in contrast it downregulated PGE2 production and cyclooxygenase-2 expression in both lung fibroblasts and macrophages. Thus the net profibrotic activity of IL-10 in vivo appears to be mediated by its ability to stimulate the expression of the profibrotic cytokine TGF-beta1 while suppressing the expression of cyclooxygenase-2 and thus production of the antifibrotic eicosanoid PGE2. These effects appear to be independent of the enhanced lung CD4+ T-lymphocytosis observed in IL-10-deficient mice.

Pulmonary overexpression of IL-10 augments lung fibrosis and Th2 responses induced by silica particles

“…Transgenic mice overexpressing IL-10 selectively in the lung via the 10-kDa Clara cell protein promoter spontaneously developed subepithelial fibrosis (36). In accordance with these data, we showed that the fibrotic response induced by silica particles was significantly less important in IL-10-deficient mice than in wildtype mice after silica treatment, suggesting that IL-10 plays a detrimental role during silica-induced fibrosis (4,27).…”

Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?

“…In accordance, IL-10 augments the fibrotic responses to inhaled silica particles as seen in IL-10 deficient mice [29] and over expression of IL-10 by adenoviral gene transfer [30]. In vitro, IL-10 also induces TGF-b1 expression in alveolar macrophages [29]. Hence, inhibition of IL-13 and IL-10 by SAHA may have additional beneficial effects in IPF.…”

“…Although delivery of IL-10 plasmid inhibits bleomycininduced pulmonary fibrosis [27], transgenic mice over expressing IL-10 develop pulmonary inflammation and subepithelial fibrosis with an accumulation of TGF-b1 [28]. In accordance, IL-10 augments the fibrotic responses to inhaled silica particles as seen in IL-10 deficient mice [29] and over expression of IL-10 by adenoviral gene transfer [30]. In vitro, IL-10 also induces TGF-b1 expression in alveolar macrophages [29].…”

Dysregulation of the immune system caused by silica and asbestos

“…Indeed, a critical study by Chen et al (1998) showed that an increased presence of TGF-β not only inhibited neutrophil (and likely macrophage) activation by FasL, but also led to a reduction in tumor (cell) rejection in the treated host. There is ample evidence that there is an increase in TGF-β expression in the lungs of silica-exposed hosts (Williams et al, 1993;Jagirdar et al, 1996;Ji et al, 2003a, b;Barbarin et al, 2004). If the TGF-β can mitigate effects of FasL so as to: (1) leave macrophage levels intact by diminishing induction of apoptosis; (2) lessen the release of select cytokines and/or chemokines that are essential to mounting an anti-tumor response (as well as being proinflammatory); and, (3) cause a shift in FasL-associated activities from an inflammatory to a suppressive function with other immune cell types needed to recognize and/or remove (silica-induced) transformed cells, this would provide a reasonable explanation for the 'time-sensitive' (re: exposure-to-tumor cell appearance) findings of Keller (1976) and those of other investigators noted above, as well as for how silica might disrupt tumor immunity in silicotic patients.…”