TAK1 inhibition prevents the development of autoimmune diabetes in NOD mice

Fei Xia,Yang Liu,Tingting Liu,Ming Xiang,Hui Cao,Jingli Lu,Jiao Du,Shouguo Wei,Xiulan Liu

doi:10.1038/srep14593

Abstract

Transforming growth factor-β activated kinase-1 (TAK1, Map3k7), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is essential in innate and adaptive immune responses. We postulated that blockade of TAK1 would affect autoimmune diabetes in non-obese diabetic (NOD) mice. Administration of 5Z-7-oxozeaenol (OZ), a TAK1 inhibitor, decreased the incidence and delayed the onset of autoimmune diabetes in both spontaneous and accelerated (cyclophosphamide-induced) experimental NOD mice. OZ also reduced insulitis, preserved islet function, increased the expression of α1- antitrypsin (AAT), and severely inhibited NF-κB and JNK/AP-1 signaling pathways in immune organs and pancreatic tissues. Importantly, TAK1 inhibition by OZ elicited a Th1 to Th2 cytokine shift, and increased TGF-β1 production in cultured T lymphocytes supernatants. Systemic TAK1 inhibition induced immature DCs with lower expressions of MHC-II and CD86, attenuated DC-mediated T cell proliferation in allogeneic MLR, and production of cytokine IL-12p70 in DCs suspensions. The results indicate that TAK1 inhibition with OZ was associated with a lower frequency of autoimmune diabetes in NOD mice. The net effect of TAK1 inhibition in NOD mice therefore appears to be protective rather than disease-enhancing. Strategies targeting TAK1 specifically in NOD mice might prove useful for the treatment of autoimmune diabetes in general.

Highlights

Immune responses[12,13,14]
In B cells and T cells, TAK1 is required for development and survival through NF-κB and MAPK pathways induced by cytokines, toll-like receptor (TLR) ligands, and T cell receptor (TCR)-or B cell receptor (BCR)[12,23,24]
The protective effect of TAK1 inhibition was not unexpected, because TAK1 is indispensable for cellular responses to Toll-like receptor ligands, CD40, and B cell receptor crosslinking, all potentially implicated in immune-related pathological processes including T1D15,16

Summary

Introduction

Many of the signaling pathways triggered by multiple extracellular stimuli converge at the level of TAK1 Those stimuli include cytokines such as interleukin-1 (IL-1), toll-like receptor (TLR), tumor necrosis factor (TNF), transforming growth factor β (TGF-β ), B cell receptor (BCR), and T cell receptor (TCR) ligands[15,16]. Activated TAK1 phosphorylates the IKK complex as well as p38, c-Jun N-terminal kinase (JNK), and extracellular signal regulated kinase (ERK), activating NF-κ B and AP-1 17. These transcription factors initiate expression of genes involved in inflammatory responses. TAK1 may negatively regulate TLR4-induced NF-κB and p38 signaling pathways during myeloid cell homeostasis[26]. The results provide evidence that TAK1 may be a potential target for treatment of T1DM

Methods

Results

Conclusion