IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway

Background: Myofibroblasts play a role in the airway remodeling response of bronchial asthma, IL-4 and IL-13 are possibly involved in the airway remod eling response by inducing extracellular matrix production by fibroblasts, However, the roles of these cytokines in inducing the phenotypic modulation of human lung fibroblasts (HLFs) to myofibroblasts and the intracellular s ignal have not been determined, Objective: We examined the effect of IL-4 and IL-13 on inducing the phenoty pic modulation of HLFs to myofibroblasts characterized by alpha -smooth mus cle actin and examined the role of the mitogen-activated protein (MAP) kina se superfamily in inducing the myofibroblastic phenotype of the HLF to clar ify these issues, Methods: Phosphorylation and activities of c-Jun NH2-terminal kinase (JNK), p38 MAP kinase, and extracellular signal-regulated kinase (Erk) were exami ned by using Western blotting. and in vitro kinase assay, Expression of a-s mooth muscle actin in IL-4- and IL-13-stimulated HLFs was analyzed by means of Western blotting, Results: The results showed that (1) IL-4 and IL-13 increased alpha -smooth muscle actin expression in a dose- and time-dependent manner; (2) IL-4 and IL-13 induced increases in JNK and Erk phosphorylation and activity but no t p38 MAP kinase activity; (3) CEP-1347 and PD 98059 attenuated IL-4- and I L13-induced JNK and Erk activity, respectively; and (4) CEP-1347, but not P D 98059, attenuated IL-4- and IL13-induced alpha -smooth muscle actin expre ssion, Conclusion: These results indicate that IL-4 and IL-13 are capable of induc ing the phenotypic modulation of HLFs to myofibroblasts, and JNK, but not p 38 MAP kinase and Erk, regulates IL-4- and IL-13-induced phenotypic modulat ion of HLFs to myofibroblasts.