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Pioglitazone alters monocyte populations and stimulates recent thymic emigrants in the BBDZR/Wor type 2 diabetes rat model.

Gao BT, Lee RP, Jiang Y, Steinle JJ, Morales-Tirado VM - Diabetol Metab Syndr (2015)

Bottom Line: Moreover, we found evidence that Pio caused a selective growth of newly differentiated T lymphocytes, based on the presence of recent thymic emigrants in vivo.To investigate effects of Pio on the inflammatory milieu, we examined the production of the signature cytokines TNF-α and IL-1β and found they were reduced by Pio-treatment, while the levels of IL-4, an anti-inflammatory mediator, were significantly increased in a Pio-dependent manner.We show for the first time that Pio treatment significantly suppresses the systemic inflammatory status in the BBDZR/Wor type 2 diabetes rat model by the selective growth of newly differentiated CD3(+) T cells and by increasing CD3(+)IL-4 production in immigrant spleen lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 USA.

ABSTRACT

Background: Type 2 diabetes is commonly characterized by insulin deficiency and decreased sensitivity of insulin receptors, leading to a chronic state of hyperglycemia in individuals. Disease progression induces changes in the immune profile that engenders a chronic inflammatory condition. Thiazolidinedione (TDZ) drugs, such as Pioglitazone (Pio), aid in controlling disease symptoms. While the mechanisms by which Pio controls hyperglycemia are beginning to be understood, relatively little is known about the effects of Pio on suppression of the systemic immune phenotype, attributed to visceral adipose tissue and macrophages.

Methods: Here, we utilize the recently developed BBDZR/Wor type 2 diabetes rat model to test our hypothesis that a selective in vivo growth of CD3(+)T cells in the spleen contributes to the increase in T lymphocytes, including Tregs, independent of visceral adipose tissue. We investigated the systemic effects of Pio on multifactorial aspects of the disease-induced immune phenotype both in vivo and in vitro in normal, non-diabetic animals and in disease.

Results: Our work revealed that Pio reversed the lymphopenic status of diabetic rats, in part by an increase in CD3(+) T lymphocytes and related subsets. Moreover, we found evidence that Pio caused a selective growth of newly differentiated T lymphocytes, based on the presence of recent thymic emigrants in vivo. To investigate effects of Pio on the inflammatory milieu, we examined the production of the signature cytokines TNF-α and IL-1β and found they were reduced by Pio-treatment, while the levels of IL-4, an anti-inflammatory mediator, were significantly increased in a Pio-dependent manner. The increase in IL-4 production, although historically attributed to macrophages from visceral adipose tissue under other conditions, came also from CD3(+) T lymphocytes from the spleen, suggesting splenocytes contribute to the Pio-induced shift towards an anti-inflammatory phenotype.

Conclusions: We show for the first time that Pio treatment significantly suppresses the systemic inflammatory status in the BBDZR/Wor type 2 diabetes rat model by the selective growth of newly differentiated CD3(+) T cells and by increasing CD3(+)IL-4 production in immigrant spleen lymphocytes.

No MeSH data available.


Related in: MedlinePlus

Reduced inflammatory phenotype in pio-treated diabetic BBDZR/Wor rats. Splenocytes from all four groups were cultured for 6 h ex vivo in the presence of Phorbol 12-myristate 13 acetate (PMA) at a concentration of 100 ng/mL. Golgi Plug was added for the last 4 h of treatment to inhibit protein transport. Cells were harvested and analyzed for different cytokines. Gates were established by using respective anti-cytokine isotype control. Upper panels are representative from n = 3 and lower panels (bar graphs) represent % ± SD. a Results for CD3+TNF-α-producers (#p < 0.005, p < 0.05); b CD3+IL-1β-producers (*p < 0.05); and c CD3+IL-4 and total IL-4 producers (#p < 0.0005, *p < 0.005, ¶p < 0.05)
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Fig2: Reduced inflammatory phenotype in pio-treated diabetic BBDZR/Wor rats. Splenocytes from all four groups were cultured for 6 h ex vivo in the presence of Phorbol 12-myristate 13 acetate (PMA) at a concentration of 100 ng/mL. Golgi Plug was added for the last 4 h of treatment to inhibit protein transport. Cells were harvested and analyzed for different cytokines. Gates were established by using respective anti-cytokine isotype control. Upper panels are representative from n = 3 and lower panels (bar graphs) represent % ± SD. a Results for CD3+TNF-α-producers (#p < 0.005, p < 0.05); b CD3+IL-1β-producers (*p < 0.05); and c CD3+IL-4 and total IL-4 producers (#p < 0.0005, *p < 0.005, ¶p < 0.05)

Mentions: As has been extensively shown and reviewed [28–34], states of obesity and hyperglycemia upregulate pro-inflammatory cytokines both locally and systemically. To confirm that the diabetic BBZDR/Wor rats exhibit these pathologic changes, we investigated the percentage of CD3+ splenocytes producing the pro-inflammatory cytokines TNF-ɑ and IL-1β. As expected, diabetic rats showed an increase in the percentage of CD3+TNF-ɑ-producing cells compared to the non-diabetic (11.7 % ± 1.2 versus 4.4 % ± 1.3, p < 0.005, Fig. 2a). Furthermore, our data suggests splenic lymphocytes contribute, at least part, to the pro-inflammatory cytokine milieu. Our results suggest that at least part of that action, in the case of Pioglitazone, is due to reduction of the CD3+ T cells that produce TNF-α and IL-1β. Diabetic rats treated with Pio had a lower percentage of CD3+TNF-α-producers (1.8 % ± 1.7 versus 11.7 % ± 1.2 in controls; p < 0.05, Fig. 2a). Similarly, CD3+IL-1β-producers were reduced from 5.0 % ± 1.4 to 1.3 % ± 1.6 (p < 0.05, Fig. 2b).Fig. 2


Pioglitazone alters monocyte populations and stimulates recent thymic emigrants in the BBDZR/Wor type 2 diabetes rat model.

Gao BT, Lee RP, Jiang Y, Steinle JJ, Morales-Tirado VM - Diabetol Metab Syndr (2015)

Reduced inflammatory phenotype in pio-treated diabetic BBDZR/Wor rats. Splenocytes from all four groups were cultured for 6 h ex vivo in the presence of Phorbol 12-myristate 13 acetate (PMA) at a concentration of 100 ng/mL. Golgi Plug was added for the last 4 h of treatment to inhibit protein transport. Cells were harvested and analyzed for different cytokines. Gates were established by using respective anti-cytokine isotype control. Upper panels are representative from n = 3 and lower panels (bar graphs) represent % ± SD. a Results for CD3+TNF-α-producers (#p < 0.005, p < 0.05); b CD3+IL-1β-producers (*p < 0.05); and c CD3+IL-4 and total IL-4 producers (#p < 0.0005, *p < 0.005, ¶p < 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4557231&req=5

Fig2: Reduced inflammatory phenotype in pio-treated diabetic BBDZR/Wor rats. Splenocytes from all four groups were cultured for 6 h ex vivo in the presence of Phorbol 12-myristate 13 acetate (PMA) at a concentration of 100 ng/mL. Golgi Plug was added for the last 4 h of treatment to inhibit protein transport. Cells were harvested and analyzed for different cytokines. Gates were established by using respective anti-cytokine isotype control. Upper panels are representative from n = 3 and lower panels (bar graphs) represent % ± SD. a Results for CD3+TNF-α-producers (#p < 0.005, p < 0.05); b CD3+IL-1β-producers (*p < 0.05); and c CD3+IL-4 and total IL-4 producers (#p < 0.0005, *p < 0.005, ¶p < 0.05)
Mentions: As has been extensively shown and reviewed [28–34], states of obesity and hyperglycemia upregulate pro-inflammatory cytokines both locally and systemically. To confirm that the diabetic BBZDR/Wor rats exhibit these pathologic changes, we investigated the percentage of CD3+ splenocytes producing the pro-inflammatory cytokines TNF-ɑ and IL-1β. As expected, diabetic rats showed an increase in the percentage of CD3+TNF-ɑ-producing cells compared to the non-diabetic (11.7 % ± 1.2 versus 4.4 % ± 1.3, p < 0.005, Fig. 2a). Furthermore, our data suggests splenic lymphocytes contribute, at least part, to the pro-inflammatory cytokine milieu. Our results suggest that at least part of that action, in the case of Pioglitazone, is due to reduction of the CD3+ T cells that produce TNF-α and IL-1β. Diabetic rats treated with Pio had a lower percentage of CD3+TNF-α-producers (1.8 % ± 1.7 versus 11.7 % ± 1.2 in controls; p < 0.05, Fig. 2a). Similarly, CD3+IL-1β-producers were reduced from 5.0 % ± 1.4 to 1.3 % ± 1.6 (p < 0.05, Fig. 2b).Fig. 2

Bottom Line: Moreover, we found evidence that Pio caused a selective growth of newly differentiated T lymphocytes, based on the presence of recent thymic emigrants in vivo.To investigate effects of Pio on the inflammatory milieu, we examined the production of the signature cytokines TNF-α and IL-1β and found they were reduced by Pio-treatment, while the levels of IL-4, an anti-inflammatory mediator, were significantly increased in a Pio-dependent manner.We show for the first time that Pio treatment significantly suppresses the systemic inflammatory status in the BBDZR/Wor type 2 diabetes rat model by the selective growth of newly differentiated CD3(+) T cells and by increasing CD3(+)IL-4 production in immigrant spleen lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163 USA.

ABSTRACT

Background: Type 2 diabetes is commonly characterized by insulin deficiency and decreased sensitivity of insulin receptors, leading to a chronic state of hyperglycemia in individuals. Disease progression induces changes in the immune profile that engenders a chronic inflammatory condition. Thiazolidinedione (TDZ) drugs, such as Pioglitazone (Pio), aid in controlling disease symptoms. While the mechanisms by which Pio controls hyperglycemia are beginning to be understood, relatively little is known about the effects of Pio on suppression of the systemic immune phenotype, attributed to visceral adipose tissue and macrophages.

Methods: Here, we utilize the recently developed BBDZR/Wor type 2 diabetes rat model to test our hypothesis that a selective in vivo growth of CD3(+)T cells in the spleen contributes to the increase in T lymphocytes, including Tregs, independent of visceral adipose tissue. We investigated the systemic effects of Pio on multifactorial aspects of the disease-induced immune phenotype both in vivo and in vitro in normal, non-diabetic animals and in disease.

Results: Our work revealed that Pio reversed the lymphopenic status of diabetic rats, in part by an increase in CD3(+) T lymphocytes and related subsets. Moreover, we found evidence that Pio caused a selective growth of newly differentiated T lymphocytes, based on the presence of recent thymic emigrants in vivo. To investigate effects of Pio on the inflammatory milieu, we examined the production of the signature cytokines TNF-α and IL-1β and found they were reduced by Pio-treatment, while the levels of IL-4, an anti-inflammatory mediator, were significantly increased in a Pio-dependent manner. The increase in IL-4 production, although historically attributed to macrophages from visceral adipose tissue under other conditions, came also from CD3(+) T lymphocytes from the spleen, suggesting splenocytes contribute to the Pio-induced shift towards an anti-inflammatory phenotype.

Conclusions: We show for the first time that Pio treatment significantly suppresses the systemic inflammatory status in the BBDZR/Wor type 2 diabetes rat model by the selective growth of newly differentiated CD3(+) T cells and by increasing CD3(+)IL-4 production in immigrant spleen lymphocytes.

No MeSH data available.


Related in: MedlinePlus