JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-kappaB activation and the JAK/STAT pathway.
JANEX-1/WHI-P131, a selective Janus kinase 3 (JAK3) inhibitor, has been shown to delay the onset of diabetes in the NOD mouse model. However, the molecular mechanism by which JANEX-1 protects pancreatic beta-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)-1beta and interferon (IFN)-gamma-induced beta-cell damage using isolated islets. JANEX-1-pretreated islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced inducible form of NO synthase (iNOS) expression, and decreased islet destruction. The molecular mechanism by which JANEX-1 inhibits iNOS expression was mediated through suppression of the nuclear factor kappaB (NF-kappaB) and JAK/signal transducer and activator of transcription (STAT) pathways. Islets treated with the cytokines downregulated the protein levels of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, but pretreatment with JANEX-1 attenuated these decreases. Additionally, islets from JAK3(-/-) mice were more resistant to cytokine toxicity than islets from control mice. These results demonstrate that JANEX-1 protects beta-cells from cytokine toxicity through suppression of the NF-kappaB and JAK/STAT pathways and upregulation of SOCS proteins, suggesting that JANEX-1 may be used to preserve functional beta-cell mass.
Lv
Na
N
Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
Kim
Eun-Kyung
EK
Song
Mi-Young
MY
Choi
Ha-Na
HN
Moon
Woo Sung
WS
Park
Sung-Joo
SJ
Park
Jin-Woo
JW
Kwon
Kang-Beom
KB
Park
Byung-Hyun
BH
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D053583:Interleukin-1beta; C507936:Jak3 protein, rat; D016328:NF-kappa B; D011799:Quinazolines; D050791:STAT Transcription Factors; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C116180:WHI P131; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3