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 remodeling 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 signal have not been determined.


OBJECTIVE
We examined the effect of IL-4 and IL-13 on inducing the phenotypic modulation of HLFs to myofibroblasts characterized by alpha-smooth muscle actin and examined the role of the mitogen-activated protein (MAP) kinase superfamily in inducing the myofibroblastic phenotype of the HLF to clarify these issues.


METHODS
Phosphorylation and activities of c-Jun NH(2)-terminal kinase (JNK), p38 MAP kinase, and extracellular signal-regulated kinase (Erk) were examined by using Western blotting and in vitro kinase assay. Expression of alpha-smooth 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 not p38 MAP kinase activity; (3) CEP-1347 and PD 98059 attenuated IL-4- and IL13-induced JNK and Erk activity, respectively; and (4) CEP-1347, but not PD 98059, attenuated IL-4- and IL-13-induced alpha-smooth muscle actin expression.


CONCLUSIONS
These results indicate that IL-4 and IL-13 are capable of inducing the phenotypic modulation of HLFs to myofibroblasts, and JNK, but not p38 MAP kinase and Erk, regulates IL-4- and IL-13-induced phenotypic modulation of HLFs to myofibroblasts.
Hashimoto
S
S
First Department of Internal Medicine Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Gon
Y
Y
Takeshita
I
I
Maruoka
S
S
Horie
T
T
D000199:Actins / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism; D010641:Phenotype; D048051:p38 Mitogen-Activated Protein Kinases
D000199:Actins; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D018793:Interleukin-13; C106592:3,9-bis((ethylthio)methyl)-K-252a; D015847:Interleukin-4; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases