Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes.
The c-Jun NH(2)-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 beta 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-gamma 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.
Jaeschke
Anja
A
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Rincón
Mercedes
M
Doran
Beth
B
Reilly
Judith
J
Neuberg
Donna
D
Greiner
Dale L
DL
Shultz
Leonard D
LD
Rossini
Aldo A
AA
Flavell
Richard A
RA
Davis
Roger J
RJ
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D007107:Immune System; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D020033:Protein Isoforms; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors
D007328:Insulin; D020033:Protein Isoforms; D048056:Mitogen-Activated Protein Kinase 9