Genistein protects pancreatic beta cells against cytokine-mediated toxicity.
In the past few decades, the use of genistein as an anti-inflammatory agent has gained much attention. Our current study focuses on the preventive effects of genistein on cytokine-induced pancreatic beta-cell damage. Treatment of RINm5F (RIN) rat insulinoma cells with interleukin (IL)-1beta and interferon (IFN)-gamma induced cell damage, which was correlated with nitric oxide (NO) production. Genistein completely prevented cytokine-mediated cytotoxicity and NO production, a finding that correlated well with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism of genistein inhibition of iNOS gene expression appeared to involve the inhibition of NFkappaB activation. The cytokine induced increases in NFkappaB binding activity, nuclear p50 and p65 subunit levels, and IkappaBalpha degradation in cytosol compared to unstimulated cells; genistein abolished all of these parameters. The cytoprotective effects of genistein are also mediated through the suppression of ERK-1/2 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. In a second set of experiments, rat islets were used. The findings on beta-cell protective effects of genistein were essentially the same as for the RIN cell data, namely genistein prevented cytokine-induced NO production, iNOS expression, ERK-1/2 activation, JAK/STAT activation, and impairment of glucose-stimulated insulin secretion. Collectively, these results suggest that genistein might be used to preserve functional beta-cell mass.
Kim
Eun-Kyung
EK
Department of Biochemistry, Medical School and Institute for Medical Sciences, Chonbuk National University, Jeonju, Jeonbuk, 561-756, Republic of Korea.
Kwon
Kang-Beom
KB
Song
Mi-Young
MY
Seo
Sang-Wan
SW
Park
Sung-Joo
SJ
Ka
Sun-O
SO
Na
Lv
L
Kim
Kyung-Ah
KA
Ryu
Do-Gon
DG
So
Hong-Seob
HS
Park
Raekil
R
Park
Jin-Woo
JW
Park
Byung-Hyun
BH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019610:Cytoprotection; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000633:toxicity; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000633:toxicity; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D050791:STAT Transcription Factors / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D009569:Nitric Oxide; D007371:Interferon-gamma; D019833:Genistein; D052247:Nitric Oxide Synthase Type II; D053612:Janus Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose