Limits...
Interferon tau alleviates obesity-induced adipose tissue inflammation and insulin resistance by regulating macrophage polarization.

Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW, Zhou B - PLoS ONE (2014)

Bottom Line: Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes.Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways.Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science, Texas A&M University, College Station, Texas, United States of America.

ABSTRACT
Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes. Currently available type I interferons for therapeutic immunomodulation are accompanied by high cytotoxicity and therefore in this study we have examined anti-inflammatory effects of interferon tau (IFNT), a member of the type I interferon family with low cellular toxicity even at high doses. Using a diet-induced obesity mouse model, we observed enhanced insulin sensitivity in obese mice administered IFNT compared to control mice, which was accompanied by a significant decrease in secretion of proinflammatory cytokines and elevated anti-inflammatory macrophages (M2) in adipose tissue. Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways. Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

Show MeSH

Related in: MedlinePlus

IFNT induces STAT1 and STAT3 activation in BMDMs.(A) The phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and (B) pSTAT1 in BMDMs was measured by flow cytometry after 90-min of LPS (100 ng/mL) or IL-4 (20 ng/mL) stimulation (n = 3). (C) The expression of interferon regulatory factor 9 (IRF9) was analyzed by qRT-PCR after 48-h LPS (100 ng/mL) or IL4 stimulation (20 ng/mL); n = 3. Data are presented as mean ± SEM. *P<0.05, **P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4048269&req=5

pone-0098835-g006: IFNT induces STAT1 and STAT3 activation in BMDMs.(A) The phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and (B) pSTAT1 in BMDMs was measured by flow cytometry after 90-min of LPS (100 ng/mL) or IL-4 (20 ng/mL) stimulation (n = 3). (C) The expression of interferon regulatory factor 9 (IRF9) was analyzed by qRT-PCR after 48-h LPS (100 ng/mL) or IL4 stimulation (20 ng/mL); n = 3. Data are presented as mean ± SEM. *P<0.05, **P<0.001.

Mentions: To understand the mechanism of IFNT action in regulating macrophage polarization, we examined signaling pathways mediated by type I interferon receptors in activated macrophages. We found that the expression of type I interferon receptor (IFNAR) was not affected by IFNT treatment in activated BMDMs (FigureS4). However, IFNT significantly enhanced STAT3 activation upon IL-4 stimulation as evidenced by significantly elevated phosphorylated STAT3 proteindetected by intracellular staining assays followed by flow cytometry analysis (Figure6A). Alternatively, type I interferons can exert anti-inflammatory functions through inducing activation of interferon-stimulated gene factor-3 (ISGF3) complex, which includes STAT1, STAT2, and interferon regulatory factor 9 (IRF9). In M2 macrophages, activation of STAT1 was increased by IFNT compared to the control (Figure6B).In LPS-stimulated BMDMs, IFNT did not affect the phosphorylation status of STAT1 or STAT3 (Figure6A, B). In addition, the abundance of IRF9 was significantly decreased in M1 macrophages, but increased in M2 macrophages in response to IFNT (Figure6C). Thus, these results suggest that IFNT may modulate macrophage polarization primarily through controlling activation of ISGF3 complex and STAT3 pathway.


Interferon tau alleviates obesity-induced adipose tissue inflammation and insulin resistance by regulating macrophage polarization.

Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW, Zhou B - PLoS ONE (2014)

IFNT induces STAT1 and STAT3 activation in BMDMs.(A) The phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and (B) pSTAT1 in BMDMs was measured by flow cytometry after 90-min of LPS (100 ng/mL) or IL-4 (20 ng/mL) stimulation (n = 3). (C) The expression of interferon regulatory factor 9 (IRF9) was analyzed by qRT-PCR after 48-h LPS (100 ng/mL) or IL4 stimulation (20 ng/mL); n = 3. Data are presented as mean ± SEM. *P<0.05, **P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048269&req=5

pone-0098835-g006: IFNT induces STAT1 and STAT3 activation in BMDMs.(A) The phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and (B) pSTAT1 in BMDMs was measured by flow cytometry after 90-min of LPS (100 ng/mL) or IL-4 (20 ng/mL) stimulation (n = 3). (C) The expression of interferon regulatory factor 9 (IRF9) was analyzed by qRT-PCR after 48-h LPS (100 ng/mL) or IL4 stimulation (20 ng/mL); n = 3. Data are presented as mean ± SEM. *P<0.05, **P<0.001.
Mentions: To understand the mechanism of IFNT action in regulating macrophage polarization, we examined signaling pathways mediated by type I interferon receptors in activated macrophages. We found that the expression of type I interferon receptor (IFNAR) was not affected by IFNT treatment in activated BMDMs (FigureS4). However, IFNT significantly enhanced STAT3 activation upon IL-4 stimulation as evidenced by significantly elevated phosphorylated STAT3 proteindetected by intracellular staining assays followed by flow cytometry analysis (Figure6A). Alternatively, type I interferons can exert anti-inflammatory functions through inducing activation of interferon-stimulated gene factor-3 (ISGF3) complex, which includes STAT1, STAT2, and interferon regulatory factor 9 (IRF9). In M2 macrophages, activation of STAT1 was increased by IFNT compared to the control (Figure6B).In LPS-stimulated BMDMs, IFNT did not affect the phosphorylation status of STAT1 or STAT3 (Figure6A, B). In addition, the abundance of IRF9 was significantly decreased in M1 macrophages, but increased in M2 macrophages in response to IFNT (Figure6C). Thus, these results suggest that IFNT may modulate macrophage polarization primarily through controlling activation of ISGF3 complex and STAT3 pathway.

Bottom Line: Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes.Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways.Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science, Texas A&M University, College Station, Texas, United States of America.

ABSTRACT
Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes. Currently available type I interferons for therapeutic immunomodulation are accompanied by high cytotoxicity and therefore in this study we have examined anti-inflammatory effects of interferon tau (IFNT), a member of the type I interferon family with low cellular toxicity even at high doses. Using a diet-induced obesity mouse model, we observed enhanced insulin sensitivity in obese mice administered IFNT compared to control mice, which was accompanied by a significant decrease in secretion of proinflammatory cytokines and elevated anti-inflammatory macrophages (M2) in adipose tissue. Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways. Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

Show MeSH
Related in: MedlinePlus