JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-[kappa]B 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 β-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)...

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Bibliographic Details
Published in:Experimental cell research 2009-07, Vol.315 (12), p.2064-2071
Main Authors: Lv, Na, Kim, Eun-Kyung, Song, Mi-Young, Choi, Ha-Na, Moon, Woo Sung, Park, Sung-Joo, Park, Jin-Woo, Kwon, Kang-Beom, Park, Byung-Hyun
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
ANTIGENS
Cellular biology
Cytokines
ELECTROPHORESIS
GLUCOSE
INSULIN
INTERFERON
MICE
Molecular biology
NITRIC OXIDE
PANCREAS
Signal transduction
TOXICITY
TRANSCRIPTION
TRANSDUCERS
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Summary: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 β-cells is unknown. In the current study, we investigated the role of JANEX-1 on interleukin (IL)-1β and interferon (IFN)-γ-induced β-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 κB (NF-κB) 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 β-cells from cytokine toxicity through suppression of the NF-κB and JAK/STAT pathways and upregulation of SOCS proteins, suggesting that JANEX-1 may be used to preserve functional β-cell mass. [PUBLICATION ABSTRACT]
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2009.04.021