Interleukin (IL)-4 and IL-13 up-regulate monocyte chemoattractant protein-1 expression in human bronchial epithelial cells: involvement of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2 and Janus kinase-2 but not c-Jun NH2-terminal kinase 1/2 signalling pathways.
The Th2 cytokines interleukin (IL)-4 and IL-13 and chemokine monocyte chemoattractant protein-1 (MCP-1) are significantly involved in bronchial hyperreactivity (BHR) and remodelling in allergic asthma. Although IL-4 and IL-13 can regulate a number of chemokines from bronchial epithelium, their regulatory effect on the expression of MCP-1 is as yet unproved. We aim to investigate the intracellular signalling mechanisms of IL-4 and IL-13 regulating the expression and secretion of MCP-1 from human bronchial epithelial cells. BEAS-2B cells, derived from a human bronchial epithelial cell line, were activated with or without IL-4 and/or IL-13 for different time intervals. MCP-1 gene expression and protein secretion were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Activation of signalling molecules p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and Janus kinase-2 (JAK-2) was accessed by Western blotting. IL-4 and IL-13 were found to up-regulate gene expression and significantly increase the release of MCP-1 from BEAS-2B cells. Both cytokines could activate p38 MAPK, ERK and JAK-2, but not JNK activity. Inhibition of p38 MAPK, ERK and JAK-2 activities by pretreating the cells with their corresponding inhibitors SB203580, PD98059 and AG490, respectively, significantly suppressed IL-4- and IL-13-induced MCP-1 production in BEAS-2B cells. Together, the above results illustrate that the activation of p38 MAPK, ERK and JAK-2 but not JNK is crucial for IL-4- and IL-13-induced MCP-1 release in human bronchial epithelial cells. Our findings may provide insight into the future development of more effective therapeutic agents for treating allergic asthma.
Ip
W K
WK
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Wong
C K
CK
Lam
C W K
CW
D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D005419:Flavonoids; D007093:Imidazoles; D018793:Interleukin-13; D007378:Interleukins; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one