Dual roles of IL-4 in lung injury and fibrosis.
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-alpha, IFN-gamma, 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, alpha-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.
Huaux
François
F
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Liu
Tianju
T
McGarry
Bridget
B
Ullenbruch
Matt
M
Phan
Sem H
SH
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001761:Bleomycin / Q000008:administration & dosage; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D001761:Bleomycin; D015847:Interleukin-4