Dual Roles of IL-4 in Lung Injury and Fibrosis

Abstract

Increased lung IL-4 expression in pulmonary fibrosis suggests a potential pathogenetic role for this cytokine. To dissect this role, bleomycin-induced pulmonary inflammation and fibrosis were analyzed and compared in wild type (IL-4+/+) vs IL-4-deficient (IL-4−/−) mice. Lethal pulmonary injury after bleomycin treatment was higher in IL-4−/− vs IL-4+/+ mice. By administration of anti-CD3 Abs, we demonstrated that this early response was linked to the marked T lymphocyte lung infiltration and to the overproduction of the proinflammatory mediators such as TNF-α, IFN-γ, and NO in IL-4−/− mice. In contrast to this early anti-inflammatory/immunosuppressive role, during later stages of fibrosis, IL-4 played a profibrotic role since IL-4−/− mice developed significantly less pulmonary fibrosis relative to IL-4+/+ mice. However, IL-4 failed to directly stimulate proliferation, α-smooth muscle actin, and type I collagen expression in lung fibroblasts isolated from the wild-type mice. Upon appropriate stimulation with other known fibrogenic cytokines, fibroblasts from IL-4−/− mice were relatively deficient in the studied parameters in comparison to fibroblasts isolated from IL-4+/+ mice. Taken together, these data suggest dual effects of IL-4 in this model of lung fibrosis: 1) limiting early recruitment of T lymphocytes, and 2) stimulation of fibrosis chronically.

Esophageal Remodeling Develops as a Consequence of Tissue Specific IL-5-Induced Eosinophilia

“…It is noteworthy that T helper cell type-2 cytokines are strongly implicated in tissue remodeling and fibrosis in other tissues. [39][40][41] In conclusion, our study demonstrates that eosinophil recruitment to the esophagus is associated with tissue remodeling. First, we show impressive collagen accumulation in the epithelial and subepithelial mucosa of esophageal biopsy specimens from human EE patients.…”

Th2-like immune response in radiation-induced lung fibrosis

“…Recent studies have shown that several Th2 cytokines are expressed in RILF. Buttner et al (9) and Huaux et al (10) reported elevated levels of the type 2 cytokine interleukin (IL)-4 in rats during RILF. Tabata et al (11) showed that all-trans-retinoic acid prevents RILF by suppressing the expression of IL-6 in mice lung tissue after irradiation.…”

IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis

“…Mouse lung fibroblasts were isolated from lung tissue by mincing and enzymatic digestion, as previously described (33). Cells were cultured in complete medium composed of DMEM supplemented with 10% FBS and antibiotics (Invitrogen).…”