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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.

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IFNT modulates macrophage polarization and cytokine profiles.The surface makers CD69, CD80, and CD86 of BMDMs were analyzed using flow cytometry after 48-hIL-4 (20 ng/mL; A) or lipopolysaccharide (LPS, 100 ng/mL; B) stimulation (n = 3). BMDMs were treated with IFNT at 5,000 antiviral units (AVU)/mL. The expression of cytokines IL-1β (C), TNF-α (D) and IL-10 (E) and peroxisome proliferator-activated receptor γ (PPARγ) (F) in BMDMs activated in the presence of IFNT (black bars) were analyzed by qRT-PCR (normalized to β-actin, n = 3) and compared to activated BMDMs with no IFNT treatment (white bars). Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001. MFI, medium fluorescence intensity.
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pone-0098835-g005: IFNT modulates macrophage polarization and cytokine profiles.The surface makers CD69, CD80, and CD86 of BMDMs were analyzed using flow cytometry after 48-hIL-4 (20 ng/mL; A) or lipopolysaccharide (LPS, 100 ng/mL; B) stimulation (n = 3). BMDMs were treated with IFNT at 5,000 antiviral units (AVU)/mL. The expression of cytokines IL-1β (C), TNF-α (D) and IL-10 (E) and peroxisome proliferator-activated receptor γ (PPARγ) (F) in BMDMs activated in the presence of IFNT (black bars) were analyzed by qRT-PCR (normalized to β-actin, n = 3) and compared to activated BMDMs with no IFNT treatment (white bars). Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001. MFI, medium fluorescence intensity.

Mentions: Given the distinct shift in activation status of adipose tissue macrophages in vivo, we further evaluated the effects of IFNT on macrophage polarization using a well-established in vitro model [36].Bone marrow-derived macrophages were treated with IFNT at various dosage in the presence of LPS (100 ng/mL) for M1 activation or IL-4 (20 ng/mL) for M2 activation and activation of associated surface antigens was determined using flow cytometry assays. M2 macrophages (IL-4 treatment) displayed a significantly enhanced activation pattern as judged by stronger induction of surface markers CD69, CD80, and CD86 at 48 h after stimulation (Figure 5A). In contrast, activation of M1 macrophages induced by LPS treatment was significantly stalled in the presence of IFNT resulting in the left shift of surface marker levels (Figure 5B). We further examined the cytokine production profiles in these M1 and M2 macrophages using qRT-PCRanalysis. As expected, IFNTsignificantly suppressed expression of proinflammatory cytokines IL-1β and TNF-α by BMDMs in response to LPS stimulation compared to control BMDMs (Figure5C, D). In addition, cells also displayed a slight increase in IL-10 upon IL-4 stimulation in the presence of IFNT (Figure5E). PPARγ is a key regulator that suppresses proinflammatory M1 and promotes anti-inflammatory M2 activation. Interestingly, IFNT did not affect IL-4-dependent PPARγexpression in M2 macrophages, but IFNT significantly increased PPARγ expressionin M1 macrophages (Figure 5F), which suggests a potent inflammatory suppressing impact of IFNT on macrophage polarization.


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 modulates macrophage polarization and cytokine profiles.The surface makers CD69, CD80, and CD86 of BMDMs were analyzed using flow cytometry after 48-hIL-4 (20 ng/mL; A) or lipopolysaccharide (LPS, 100 ng/mL; B) stimulation (n = 3). BMDMs were treated with IFNT at 5,000 antiviral units (AVU)/mL. The expression of cytokines IL-1β (C), TNF-α (D) and IL-10 (E) and peroxisome proliferator-activated receptor γ (PPARγ) (F) in BMDMs activated in the presence of IFNT (black bars) were analyzed by qRT-PCR (normalized to β-actin, n = 3) and compared to activated BMDMs with no IFNT treatment (white bars). Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001. MFI, medium fluorescence intensity.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098835-g005: IFNT modulates macrophage polarization and cytokine profiles.The surface makers CD69, CD80, and CD86 of BMDMs were analyzed using flow cytometry after 48-hIL-4 (20 ng/mL; A) or lipopolysaccharide (LPS, 100 ng/mL; B) stimulation (n = 3). BMDMs were treated with IFNT at 5,000 antiviral units (AVU)/mL. The expression of cytokines IL-1β (C), TNF-α (D) and IL-10 (E) and peroxisome proliferator-activated receptor γ (PPARγ) (F) in BMDMs activated in the presence of IFNT (black bars) were analyzed by qRT-PCR (normalized to β-actin, n = 3) and compared to activated BMDMs with no IFNT treatment (white bars). Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001. MFI, medium fluorescence intensity.
Mentions: Given the distinct shift in activation status of adipose tissue macrophages in vivo, we further evaluated the effects of IFNT on macrophage polarization using a well-established in vitro model [36].Bone marrow-derived macrophages were treated with IFNT at various dosage in the presence of LPS (100 ng/mL) for M1 activation or IL-4 (20 ng/mL) for M2 activation and activation of associated surface antigens was determined using flow cytometry assays. M2 macrophages (IL-4 treatment) displayed a significantly enhanced activation pattern as judged by stronger induction of surface markers CD69, CD80, and CD86 at 48 h after stimulation (Figure 5A). In contrast, activation of M1 macrophages induced by LPS treatment was significantly stalled in the presence of IFNT resulting in the left shift of surface marker levels (Figure 5B). We further examined the cytokine production profiles in these M1 and M2 macrophages using qRT-PCRanalysis. As expected, IFNTsignificantly suppressed expression of proinflammatory cytokines IL-1β and TNF-α by BMDMs in response to LPS stimulation compared to control BMDMs (Figure5C, D). In addition, cells also displayed a slight increase in IL-10 upon IL-4 stimulation in the presence of IFNT (Figure5E). PPARγ is a key regulator that suppresses proinflammatory M1 and promotes anti-inflammatory M2 activation. Interestingly, IFNT did not affect IL-4-dependent PPARγexpression in M2 macrophages, but IFNT significantly increased PPARγ expressionin M1 macrophages (Figure 5F), which suggests a potent inflammatory suppressing impact of IFNT on macrophage polarization.

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