Interferon-alpha inhibits adipogenesis via regulation of JAK/STAT1 signaling.

BACKGROUND INFORMATION: Adipose tissue regulates energy metabolism by means of adipocyte hypertrophy and/or the differentiation of pre-existing adipocytes. Excessive production of some cytokines in adipose tissue is known to be a negative regulator of adipocyte differentiation, and the resulting impaired adipogenesis contributes to disorders like insulin resistance. IFN-α is a key immunoregulatory cytokine in the development of type 1 diabetes, lipid disorders and insulin resistance; however, its effect on adipogenesis remains unknown. METHOD: We examined the effect of IFN-α on adipocyte differentiation and its mechanisms. The effect of IFN-α on adipogenesis was evaluated by Western blotting, qRT-PCR, flow cytometric analysis and Oil Red O staining. We also investigated the role of STAT1 in adipogenesis using gene silencing analysis. RESULTS: IFN-α inhibited the accumulation of lipid droplets and the expression of adipogenesis related genes. The inhibition of adipocyte differentiation by IFN-α occurred in the early stages of differentiation. IFN-α arrested the cell cycle at the G0/G1 phase and regulated the expression of CDK2 and p21. These results were confirmed in MEF cells. Treatment with IFN-α increased STAT1 phosphorylation, and STAT1 siRNA or inhibitor prevented IFN-α from inhibiting the expression of PPARγ and C/EBPα as well as cell cycle progression in 3T3-L1 cells. CONCLUSION: We suggest that IFN-α inhibits adipocyte differentiation during the early stage of adipogenesis by regulating the expression of PPARγ and C/EBPα as well as the cell cycle through JAK/STAT1 signaling pathways. GENERAL SIGNIFICANCE: Our study provides new insights into possible mechanisms of the anti-adipogenetic effects of IFN-α.

Inhibition of LPS-induced inflammatory mediators by 3-hydroxyanthranilic acid in macrophages through suppression of PI3K/NF-κB signaling pathways.

Many tryptophan metabolites have immunomodulatory effects on various immune cells. 3-Hydroxyanthranilic Acid (3-HAA) is a tryptophan metabolite reported to have anti-inflammatory activity. The mechanism of this activity is unclear. The present study examined the immunomodulatory effects and molecular mechanisms of 3-HAA on macrophages. Pretreatment of 3-HAA (0.1-10 µg mL(-1)) for 2 h markedly inhibited NO and cytokine production in LPS-stimulated Raw 264.7 cells. Moreover, translocation and activation of NF-κB by LPS in the nucleus were abrogated through the prevention of IκB degradation by 3-HAA treatment. 3-HAA significantly suppressed LPS-induced PI3K/Akt/mTOR activation, whereas MAPKs were not affected by 3-HAA treatment. Furthermore, the inhibition of mTOR by 3-HAA resulted in decreased production of inflammatory mediators and NF-κB activity. Similar results were also observed in primary peritoneal macrophages. Furthermore, 3-HAA modulated macrophage polarization. Collectively, the results suggest that 3-HAA has an immunomodulatory effect that may result from inhibition of PI3K/Akt/mTOR and NF-κB activation, thereby decreasing the production of pro-inflammatory mediators.

Inhibition of VCAM-1 expression on mouse vascular smooth muscle cells by lobastin via downregulation of p38, ERK 1/2 and NF-κB signaling pathways.

Atherosclerosis is a chronic inflammatory disease, the progression of which is associated with the increased expression of cell adhesion molecules on vascular smooth muscle cells (VSMCs). Lobastin is a new pseudodepsidone isolated from Stereocaulon alpinum, Antarctic lichen, which is known to have antioxidant and antibacterial activities. However, the nature of the biological effects of lobastin still remains unclear. In the present study, we examine the effect of lobastin on the expression of vascular cell adhesion molecules (VCAM-1) induced by TNF-α in the cultured mouse VSMC cell line, MOVAS-1. Pretreatment of VSMCs for 2 h with lobastin (0.1-10 µg/ml) concentration-dependently inhibited TNF-α-induced protein expression of VCAM-1. Lobastin also inhibited TNF-α-induced production of intracellular reactive oxygen species (ROS). Lobastin abrogated TNF-α-induced phosphorylation of p38 and ERK 1/2, but not JNK, and also inhibited TNF-α-induced NK-κB activation. In addition, lobastin suppressed TNF-α-induced IκB kinase activation, subsequent degradation of IκBα and nuclear translocation of p65 NF-κB. Our results indicate that lobastin downregulates the TNF-α-mediated induction of VCAM-1 in VSMC by inhibiting the p38, ERK 1/2 and NF-κB signaling pathways and intracellular ROS generation. Thus, lobastin may be an important regulator of inflammation in the atherosclerotic lesion and a novel therapeutic drug for the treatment of atherosclerosis.