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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0507v1 202/1/65    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kang, J.-H. Articles by Kim, M.-J. Search for Related Content PubMed PubMed Citation Articles by Kang, J.-H. Articles by Kim, M.-J.

J Kang, Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of
S Chang, Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of
H Jang, Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of
D Kim, Internal Medicine, College of Medicine, The Catholic University of Korea, Korea, Korea, Republic of
G Ryu, Internal Medicine, College of Medicine, The Catholic University of Korea, Korea, Korea, Republic of
S Ko, Internal Medicine, College of Medicine, The Catholic University of Korea, Korea, Korea, Republic of
I Jeong, Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea, Republic of
Y Jo, Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of
M Kim, Physiology, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Korea, Republic of

Correspondence: Myung-Jun Kim, Email: mjunkim{at}catholic.ac.kr

Cytokines such as IL-1β stimulate iNOS expression and NO overproduction leading to the β-cell damage. Meanwhile, glucagon-like peptide-1 (GLP-1) and its potent analog exendin-4 (EX-4) were well known for β-cell proliferation. However, the protective mechanisms of GLP-1 in β-cells exposed to cytokines were not fully elucidated. Therefore, the effects of EX-4 on the IL-1β-induced iNOS gene expression were investigated employing RINm5F β-cells. EX-4 inhibited IL-1β-induced iNOS protein expression and nitrite production. However, Northern blot and promoter analyses showed that EX-4 failed to inhibit IL-1β-induced iNOS mRNA expression and iNOS promoter activity. By EMSA, EX-4 did not alter the binding activity of NF-B to the iNOS promoter. Consistent with the EMSA result, EX-4 did not inhibit nuclear translocation of p65. We also tested the effect of EX-4 on iNOS mRNA stability. Actinomycin D chase experiments showed that EX-4 did not affect the decay rate of iNOS mRNA and the promoter assay using the construct containing 3'-untranslated region of iNOS showed that EX-4 did not alter the stability of iNOS mRNA. Meanwhile, forskolin significantly inhibited IL-1β-induced iNOS protein, which was reversed by H-89, a PKA inhibitor. Moreover, EX-4 pretreatment restored IL-1β-induced decrease in cAMP toward control level. Additionally, cycloheximide chase study demonstrated that EX-4 significantly accelerated iNOS protein degradation. We, therefore, concluded that EX-4 inhibited IL-1β-induced iNOS protein and nitrite production via cAMP/PKA system irrespective of both transcriptional and posttranscriptional mechanisms of iNOS gene and this inhibitory effect of EX-4 appears to be regulated at posttranslational level.