Interleukin-12 (IL-12)/STAT4 Axis Is an Important Element for β-Cell Dysfunction Induced by Inflammatory Cytokines

Weaver, Jessica L.; Nadler, Jerry L.; Taylor‐Fishwick, David A.

doi:10.1371/journal.pone.0142735

Cited by 28 publications

(16 citation statements)

References 58 publications

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“…Generally, the IL-12Rβ2/ JAK2/STAT4 pathway and its activated IFN-gama play a major role in common bioactivities of IL-12, while IL-12Rβ1 was appeared be not found direct function except indispensable subunit responsible for binding IL-12 [36]. But more and more researches indicated that IL-12Rβ1,in single or in aiding IL-12 signalling, vary with cells-type, has many unknown functions [37].…”

Section: Discussionmentioning

confidence: 99%

Osteogenic Effects of IL-12 on Bone Marrow Mesenchymal Stem Cells Facilitates Its Irradiation Hematopoiesis Recovery

Zhang

et al. 2020

Preprint

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Background Impaired osteogenesis differentiation of bone marrow mesenchymal stem cells (BM-MSCs) results inefficient physical supporting of hematopoietic niche and further counts against hematopoiesis recovery in radiotherapy. Interleukin-12 (IL-12) holds facilitations on acute irradiation hematopoietic recovery, but the mechanisms remain to be clarifiedAim To investigated the osteogenic effects of IL-12 on BM-MSCs and the relationship between IL-12’s osteogenic effects of BM-MSCs and its hematopoietic supportive role.Methold The osteogenic effects of IL-12 in vivo were investigated by estimating the osteoblasts in femurs of Balb/c mice after 5 Gy 60 Co-γ irradiation, and the osteogenic effects of IL-12 in vitro were investigated by analyzing the osteogentic genes and calcium mineral deposits formations in BM-MSCs after 9 Gy 60 Co-γirradaition at different times of co-culturing with IL-12 in osteogenic induction medium. For the latter, the special siRNA of IL-12 receptor 1 (IL-12Rβ1), tyrosine kinase 2 (TYK2) and the inhibitor of signal transducer and activator of transcription3 (STAT3) were used to explore the possible mechanism. The bone marrow hematopoietic supportive role of cells co-cultured with IL-12 were also investigated by analyzing the clone-forming of hematopoietic progenitor/ stem cells (HSPCs).Results Interleukin-12 (IL-12) holds facilitaties on acute irradiation-induced hematopoietic and osteogenesis damages in Balb/c mice. IL-12 also promoted osteogenesis differentiation of irradiated BM-MSCs, and for that, especially during early period after irradiation, the IL-12 receptor 1 (IL-12Rβ1)/ tyrosine kinase 2 (TYK2)/ signal transducer and activator of transcription3 (STAT3) signaling played a crucial role. That was reflected by obvious synchronicity between the upregulation time of IL-12Rβ1 and the time of the better IL-12 induced osteogenesis of BM-MSCs. The more osteogenic genes expressions and more calcium mineral deposits formations in BM-MSCs were obtained in cells co-cultured with IL-12 within 1 hour after irradiation; Beside that IL-12 increased the phosphotyrosine of STAT 3 (p-STAT3) which along with IL-12 induced osteogenesis promotions were abrogated by using IL-12Rβ1 and Tyk2 silencing RNA (siRNA) or inhibitor of STAT3. Further, the clone-forming of hematopoietic progenitor/ stem cells (HSPCs) showed much better in IL-12-BM-MSCs transplanted femurs of irradiated mice than that of BM-MSCs, even cells were co-cultured with IL-12 for only 24 hours.Conclusion IL-12 may assist hematopoiesis recovery through its early osteogenic differentiation promotion of BM-MSCs after irradiation, which suggested potential therapeutic targets of bone marrow hematopoietic damages after radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Osteogenic Effects of IL-12 on Bone Marrow Mesenchymal Stem Cells Facilitates Its Irradiation Hematopoiesis Recovery

Zhang

et al. 2020

Preprint

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“…STAT4 can be activated by IL-12, which is produced by antigen-presenting cells (APCs) and cells that have similar function as APCs; activated STAT4 can promote inflammatory cells like NK cells to produce IFN-γ. 45 Recent studies have suggested that IFN-γ can induce cells to undergo apoptosis through the change of microenvironment 46 and induced autophagy. 47 As an authorized activator of STAT4, IL-12 has the potential to evolve as a hot point in the STAT4-targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological significance of STAT4 in hepatocellular carcinoma and its effect on cell growth and apoptosis

Liang

Liu

et al. 2016

OTT

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BackgroundRecent studies showed that signal transducer and activator of transcription 4 (STAT4) was downregulated in hepatocellular carcinoma (HCC) tissues. However, the role of STAT4 in HCC is still unknown. The aim of this study is to explore the association between STAT4 expression and other clinicopathological features in HCC and to test the effect of STAT4 on cell growth and apoptosis in vitro.MethodsSTAT4 was evaluated by immunohistochemistry in 171 HCC and corresponding paraneoplastic liver, 37 cirrhosis, and 33 normal liver tissues. Association between STAT4 and clinicopathological parameters was analyzed. Meta-analysis on STAT4 in cancer was performed. The effect of STAT4 small interfering RNA (siRNA) on cell growth and cell apoptosis was also detected.ResultsPositive rate of STAT4 was 29.2% (50/171) in HCC tissues, 53.2% (91/171) in paraneoplastic liver tissues, 64.9% (24/37) in cirrhosis tissues, and 72.7% (24/33) in normal liver tissues. STAT4 was upregulated in younger patients who were female, with single tumor node, early TNM stage, without portal vein tumor embolus, and α-fetoprotein (AFP)-positive tumors compared with the groups comprising older patients, males, and those with multiple tumor nodes, advanced TNM stage, with portal vein tumor embolus, and AFP negative tumors. Meta-analysis showed STAT4 was correlated with TNM stage (OR =0.50, 95% CI =0.30, 0.83, P=0.008) and age (OR =0.58, 95% CI =0.38, 0.95, P=0.032) in malignant tissues, and with AFP level (OR =1.76, 95% CI =1.06, 2.94, P=0.03) in HCC. STAT4 siRNA promoted growth and suppressed apoptosis of HepG2 cells.ConclusionSTAT4 might play a vital role in development of HCC, via influencing cell growth and apoptosis, as a tumor suppressor.

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“…The response of islets and β-cells to the inflammatory cytokines weakens the cell viability and function and increases the induction of apoptosis. The IL12/STAT4 axis was found to induce β-cell apoptosis [111]. Serum levels of IFNγ and IL12 are reduced in Stat4 −/− NOD (non-obese diabetic) mice, and the development of diabetes in NOD mice is prevented with the absence of Stat4.…”

Section: T1dmentioning

confidence: 99%

STAT4: an immunoregulator contributing to diverse human diseases

Yang¹,

Mai²,

Peng³

et al. 2020

Int. J. Biol. Sci.

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Signal transducer and activator of transcription 4 (STAT4) is a member of the STAT family and localizes to the cytoplasm. STAT4 is phosphorylated after a variety of cytokines bind to the membrane, and then dimerized STAT4 translocates to the nucleus to regulate gene expression. We reviewed the essential role played by STAT4 in a wide variety of cells and the pathogenesis of diverse human diseases, especially many kinds of autoimmune and inflammatory diseases, via activation by different cytokines through the Janus kinase (JAK)-STAT signaling pathway.

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Interleukin-12 (IL-12)/STAT4 Axis Is an Important Element for β-Cell Dysfunction Induced by Inflammatory Cytokines

Cited by 28 publications

References 58 publications

Osteogenic Effects of IL-12 on Bone Marrow Mesenchymal Stem Cells Facilitates Its Irradiation Hematopoiesis Recovery

Osteogenic Effects of IL-12 on Bone Marrow Mesenchymal Stem Cells Facilitates Its Irradiation Hematopoiesis Recovery

Clinicopathological significance of STAT4 in hepatocellular carcinoma and its effect on cell growth and apoptosis

STAT4: an immunoregulator contributing to diverse human diseases

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