RGD Reference Report - JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-kappaB activation and the JAK/STAT pathway. - Rat Genome Database

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JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-kappaB activation and the JAK/STAT pathway.

Authors: Lv, N  Kim, EK  Song, MY  Choi, HN  Moon, WS  Park, SJ  Park, JW  Kwon, KB  Park, BH 
Citation: Lv N, etal., Exp Cell Res. 2009 Jul 15;315(12):2064-71. doi: 10.1016/j.yexcr.2009.04.021. Epub 2009 May 3.
RGD ID: 10402041
Pubmed: PMID:19414010   (View Abstract at PubMed)
DOI: DOI:10.1016/j.yexcr.2009.04.021   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cytosol located_inIDA 10402041PMID:19414010MGI 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
DNA binding enablesIDA 10402041PMID:19414010MGI 

Objects Annotated

Genes (Rattus norvegicus)
Nfkb1  (nuclear factor kappa B subunit 1)
Nfkbia  (NFKB inhibitor alpha)
Nos2  (nitric oxide synthase 2)
Socs1  (suppressor of cytokine signaling 1)
Stat1  (signal transducer and activator of transcription 1)
Stat3  (signal transducer and activator of transcription 3)
Stat4  (signal transducer and activator of transcription 4)
Stat5a  (signal transducer and activator of transcription 5A)


Additional Information