Allograft Inflammatory Factor-1 Mediates Macrophage-Induced Impairment of Insulin Signaling in Adipocytes

Abstract

Background/Aims: Allograft inflammatory factor-1 (AIF-1) is an inflammatory cytokine produced mainly by macrophages within human white adipose tissue. Its expression is increased in obese subjects and positively correlated with insulin resistance. The purpose of this study is to characterize the regulatory role of AIF-1 in insulin signaling of adipocyte. Methods: AIF-1 was over-expressed via transfection of AIF-1 cDNA into murine RAW 264.7 macrophages, and the constitutive expression of AIF-1 was decreased via transfection of targeting siRNA. Murine 3T3L1 adipocytes were treated with macrophage-conditioned medium or AIF-1 protein. Intracellular lipid accumulation was assayed by oil red O stain. Reactive oxygen species production was determinated by a flow cytometer and adipokine secretion was measured with ELISA. Glucose uptake was detected using the glucose oxidase method and insulin-signal-transduction related molecules were analyzed by Western blot. Results: Short term (48 h) AIF-1 treatment slightly promoted intracellular lipid storage in differentiating 3T3L1 cells. The protein stimulated reactive oxygen species production, provoked TNFα, IL6, resistin, but suppressed adiponectin release and insulin-stimulated glucose uptake both under normal basal and insulin resistance conditions. Furthermore, AIF-1 induced NF-κB activation, inhibited PPARγ expression, GLUT4 translocation to plasma membrane and Akt phosphorylation. Conclusion: Macrophage-derived AIF-1 up-regulated reactive oxygen species production, adipokine TNFα, IL6, resistin release, and inhibited adiponectin secretion. Moreover, it suppressed insulin-stimulated glucose uptake by down-regulating insulin signaling. Thus, AIF-1 could be related to obesity-related diseases.

Role of allograft inflammatory factor‐1 in the regulation of inflammation and oxidative stress in primary peritoneal mesothelial cells

“…However, the effect of AIF-1 on NF-kB pathway and inflammation can be alleviated by the BAY 11-7082, a NF-kB signaling inhibitor. It is consistent with that BAY 11-7082 has been reported to attenuate the elevated levels of IL-6 and TNF-a (Kumar et al, 2012;Ren et al, 2018;Zabrodskii et al, 2018). Previous studies have demonstrated that AIF-1 is encoded in the region of chromosome 6p21.3, which is clustered with genes related to the inflammatory responses in human (Iris et al, 1993;Deininger et al, 2002).…”

“…Interestingly, the production of IL-6 and TNF-a were decreased after BAY 11-7082 treatment. It is consistent with that BAY 11-7082 has been reported to attenuate the elevated levels of IL-6 and TNF-a (Kumar et al, 2012;Ren et al, 2018;Zabrodskii et al, 2018). Specifically, data revealed that peritoneal mesothelial cells, as an important cellular model, were shown to be related with fibrotic change in mouse peritoneal mesothelial cells (Bot et al, 2003;Shin et al, 2017;Zhang et al, 2018).…”

“…In addition, via exogenous AIF-1 protein supplementation, it stimulated the activation of NF-kB pathway and then promoted inflammation in the cells. In this regard, Ren et al have proved that AIF-1 treatment promoted, TNFa, induced NF-kB activation in 3T3L1 cells (Ren et al, 2018). Taken together, these findings suggest that AIF-1 as an important molecule can mediate oxidative stress and the activation of NF-kB pathway in regulating inflammation in peritoneal fibrosis tissues.…”

“…Subsequent study also indicated that AIF-1 could induce NF-kB pathway activation. In this regard, Ren et al have proved that AIF-1 treatment promoted, TNFa, induced NF-kB activation in 3T3L1 cells (Ren et al, 2018). Interestingly, the production of IL-6 and TNF-a were decreased after BAY 11-7082 treatment.…”

Staphylococcal enterotoxin U promotes proinflammatory activity of macrophage via up‐regulation of allograft inflammatory factor 1 expression

“…Short interference RNA for allograft inflammatory factor 1 (AIF-1) was synthesized (targeted sequence CCTAGAGCTGAAGAGATTA, siAIF-1) with negative control (target sequence: TTCTCCGAACGTGTCACGT, siRNA) as we previously described (Ren, Lin, Tang, Yue, & Zhao, 2018). The RNA was transfected into macrophage RAW264.7 with a Sofast kit (Xiamen, Fujian, China) according to the manufacturer's instructions.…”