A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

Abstract

The p40 subunit of IL-12 (IL-12p40), but not the heterodimeric form IL-12p70, is secreted during the development of silica-induced lung fibrosis in C57BL/6 mice. To delineate the contribution of IL-12p40 to the lung inflammatory and fibrotic processes, we compared the pulmonary responses with silica particles of IL-12p35-deficient mice (IL-12p35−/−, able to produce IL-12p40) and IL-12p40-deficient mice (IL-12p40−/−). IL-12p35−/− and IL-12p40−/− animals developed strikingly contrasting responses to silica in comparison with wild-type C57BL/6 mice. Although the IL-12p40−/− mice exhibited limited inflammatory and fibrotic reactions, the IL-12p35−/− mice presented a robust and well-developed pulmonary inflammation and fibrosis. Furthermore, the silica-induced increase in lung IL-12p40 content was significantly higher in IL-12p35−/− mice than in wild-type controls, and was associated with extensive lung fibrosis and pulmonary macrophage infiltration. The contrasting responses observed between these two IL-12 subunit-deficient murine strains were not accompanied by a strict type 1 or type 2 polarization as estimated by the measurements of lung IFN-γ/IgG2a and IL-4/IgG1 content. In vitro proliferation, type I collagen expression, as well as myofibroblast differentiation of purified pulmonary fibroblasts were not affected by treatment with exogenous rIL-12p40. In vivo, supplementation with rIL-12p40 restored the impaired pulmonary fibrotic response and macrophage accumulation in silica-treated IL-12p40−/− mice, and also promoted fibrosis and macrophage influx in wild-type mice. Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment.

Lung-Restricted Macrophage Activation in the Pearl Mouse Model of Hermansky-Pudlak Syndrome

“…The imbalance of proinflammatory and counterregulatory factors, including TNF-␣ and soluble TNFRs have also been implicated in the pathogenesis of a variety of fibrotic disorders in both humans and in animal models (35)(36)(37). Specifically, overexpression of IL-12p40-related cytokines have been reported in fibrogenic Th1-mediated autoimmune and chronic inflammatory diseases, including glomerulonephritis (39), as well as in experimental models of pulmonary fibrosis (42). Therefore, our findings of excessive production of TNF-␣, sTNFr1, sTNFr2, and IL-12p40 in pearl and pale ear mice and from their AMs ex vivo suggest a potential link between the pro and anti-inflammatory imbalance and fibrogenesis.…”

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

“…Fibronectin and type I collagen contents were measured in lung homogenates by standardized ELISA as detailed in a previous study (23,25).…”

Serum neopterin in workers exposed to inorganic dust containing free crystalline silicon dioxide

“…Disbalance in the immune response regulation is suggested [8][9][10][11][12][13]. Enhanced levels of interferon-gamma (IFN-γ), IL-12p40 messenger ribonucleic acid (mRNA) and proteins have been observed in an experimental model of silicosis, suggesting that a T-helper (Th)-1 lymphocyte subpopulation might dominate in this disease.…”