Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes

doi:10.1073/pnas.0502143102

Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes

^*Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605; ^†Section of Immunology, Department of Medicine, University of Vermont Medical School, Burlington, VT 05405; ^‡Department of Biostatistical Science, Dana Farber Cancer Institute, Boston, MA 02115; ^§Program in Molecular Medicine and Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; ^¶The Jackson Laboratory, Bar Harbor, ME 04609; and ^∥Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

Contributed by Richard A. Flavell, March 15, 2005

Abstract

The c-Jun NH₂-terminal kinase isoform (JNK) 1 is implicated in type 2 diabetes. However, a potential role for the JNK2 protein kinase in diabetes has not been established. Here, we demonstrate that JNK2 may play an important role in type 1 (insulin-dependent) diabetes that is caused by autoimmune destruction of β cells. Studies of nonobese diabetic mice demonstrated that disruption of the Mapk9 gene (which encodes the JNK2 protein kinase) decreased destructive insulitis and reduced disease progression to diabetes. CD4⁺ T cells from JNK2-deficient nonobese diabetic mice produced less IFN-γ but significantly increased amounts of IL-4 and IL-5, indicating polarization toward the Th2 phenotype. This role of JNK2 to control the Th1/Th2 balance of the immune response represents a mechanism of protection against autoimmune diabetes. We conclude that JNK protein kinases may have important roles in diabetes, including functions of JNK1 in type 2 diabetes and JNK2 in type 1 diabetes.

Footnotes

↵ ** To whom correspondence should be addressed. E-mail: roger.davis{at}umassmed.edu.
Abbreviations: JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NOD, nonobese diabetic.