Tyrphostin AG490 agent modestly but significantly prevents onset of type 1 in NOD mouse; implication of immunologic and metabolic effects of a Jak-Stat pathway inhibitor.
Previously, we have reported that the Jak-Stat signaling pathway is defective in NOD mice. In this study, prediabetic female NOD mice (4 weeks) were treated by intraperitoneal injection either with AG490 or DMSO three times per week for 4 consecutive weeks, followed by once a week for an additional 6 weeks. The onset of diabetes was attenuated in NOD mice treated with AG490 relative to DMSO treated control mice (p < 0.02). From an immunological standpoint, AG490 induced the expression of Foxp3 in CD4(+)CD25(-) T-cells and down-regulated expression of co-stimulatory molecules in dendritic cells (DC) both in vitro and in vivo. AG490 treated CD4+CD25- T-cells and DC in vitro, acquired regulatory functions; namely, the ability to suppress proliferation of a responding cell population in vitro. AG490 treatment resulted in significant reduction of blood glucose values and increased expression of PPARγ in splenocytes and markedly increased expression PPARγ2 but not PPARγ1 in adipocyte in vitro. Presence of multiple Stat5 DNA binding consensus sequences within the promoter region of the PPARγ gene in human and in mouse suggests that PPARγ is downstream to the Jak-Stat signaling pathway. This study highlights a critical role of the Jak-Stat signaling pathway in the pathogenesis of T1D and suggests that blocking the Jak-Stat signaling pathway by AG490 as a tyrosine kinase inhibitor may provide an effective means for preventing autoimmune T1D via both immunological and metabolic effects.
Department of Pharmacotherapy and Translational Research, College of Pharmacy, Gainesville, FL, USA. davoodi_semiromi@yahoo.com
Abdoreza
A
Davoodi-Semiromi
Azadeh
A
Hassanzadeh
Clive H
CH
Wasserfall
Andrew
A
Droney
Mark
M
Atkinson
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D047495:PPAR gamma / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D050791:STAT Transcription Factors / Q000276:immunology; D020032:Tyrphostins / Q000627:therapeutic use*
D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases