MEKK3 overexpression contributes to the hyperresponsiveness of IL-12-overproducing cells and CD4+ T conventional cells in nonobese diabetic mice.
Elevated IL-12 production and higher rate of CD4(+) T conventional (Tconv) cell proliferation in NOD mice have been implicated in the progression of type 1 diabetes. However, the underlying mechanisms remain largely unknown, even though enhanced activation of the IkappaB kinase (IKK)/NF-kappaB pathway has been revealed to mediate IL-12 overproduction. In this study, we report that deviated p38 MAPK activation also contributes to elevated IL-12 production with a mechanism involving MAPK-activated protein kinase-2-mediated stabilization of IL-12p40 mRNA. Aberrant p38 activation induced by various inflammatory stimuli in IL-12-overproducing cells is not due to defective MAPK phosphatase-1 induction in NOD mice. Deviated IKK and MAPKs activation also occurs in NOD CD4(+) Tconv cells, which is associated with higher rates of proliferation. All of the above evidence suggests that the signaling defects occur at the level of MAPK kinase kinase (MAK3K or MEKK). Further exploration shows that MEKK3, but not other MAP3Ks, is overexpressed in NOD IL-12-overproducing cells and CD4(+) Tconv cells independent of autoimmune inflammation. MEKK3 knockdown leads to reversal of the deviated IKK and MAPKs activation, resulting in reduced IL-12 production and decreased CD4(+) Tconv cell proliferation. Thus, this study provides a molecular mechanism of the hyperresponsiveness of IL-12-overproducing cells and CD4(+) Tconv cells in NOD mice.
Zhang
Jiyan
J
Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China. zhangjy@nic.bmi.ac.cn
Zhu
Ning
N
Wang
Qingyang
Q
Wang
Jing
J
Ma
Yuanfang
Y
Qiao
Chunxia
C
Li
Yan
Y
Li
Xinying
X
Su
Bing
B
Shen
Beifen
B
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D051550:I-kappa B Kinase / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D048748:MAP Kinase Kinase Kinase 3 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008070:Lipopolysaccharides; D018664:Interleukin-12; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse