S. Hashimoto et al., IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway, J ALLERG CL, 107(6), 2001, pp. 1001-1008
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.