Interleukin-17--induced interleukin-8 release in human airway smooth muscle cells: role for mitogen-activated kinases and nuclear factor-kappaB.
BACKGROUND
It has recently become clear that interleukin (IL)-8 plays a role in chronic neutrophilic inflammatory disorders, such as chronic rejection after lung transplantation. We have shown that IL-17--stimulated human airway smooth muscle cells (HASMC) are able to produce IL-8. The aim of this study was to determine whether p38 mitogen-activated protein kinase (MAPK), c-Jun amino-terminal kinase (JNK), p42/p44 extracellular signal-related kinase (ERK) and nuclear factor-kappaB (NF-kappaB) are involved in IL-17--induced IL-8 production in HASMC in vitro.


METHODS
We used human airway smooth muscle cells in culture. Western blotting was done to obtain data regarding activation of MAPK. Furthermore, we used specific inhibitors of MAPK to investigate their involvement in IL-17--induced IL-8 release, which was measured by enzyme-linked immunosorbent assay (ELISA).


RESULTS
Western blotting clearly demonstrated that p38 MAPK, JNK and p42/p44 ERK were activated by IL-17 in HASMC. Using SB203580, a specific inhibitor of p38 MAPK, we detected a concentration-dependent inhibition of IL-17--induced IL-8 production with a maximal decrease of 63 +/- 5% (n=8, p<0.01). Curcumin, a specific inhibitor of JNK, also concentration-dependently reduced IL-17--induced IL-8 production, with a maximal decrease of 82+/-4% (n=8, p<0.01). U0126, a specific inhibitor of p42/p44 ERK, induced a maximal decrease of 84+/-5% (n=8, p<0.001). Pyrrolydine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, caused a 70+/-5% (n=8, p<0.01) decrease in IL-17--induced IL-8 production.


CONCLUSIONS
We found that IL-17 induces activation of p38MAPK, JNK and p42/p44ERK in HASMC. We also found that p38MAPK, JNK, p42/p44 ERK and NF-kappaB play an important role in IL-17--induced IL-8 production in HASMC in vitro. This may open up new opportunities for further treatment of this disease.
Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium.
Wim A
WA
Wuyts
Bart M
BM
Vanaudenaerde
Lieven J
LJ
Dupont
Dirk E
DE
Van Raemdonck
Maurits G
MG
Demedts
Geert M
GM
Verleden
D015153:Blotting, Western; D001980:Bronchi; D002478:Cells, Cultured; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D020381:Interleukin-17; D016209:Interleukin-8; D016328:NF-kappa B; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases