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Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

ABSTRACT: Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT/MIF-2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF-2 levels were increased in the peritoneal fluid of LPS-challenged wild-type mice, yet, in visceral WAT, the proteins were differentially regulated, with elevated MIF but downregulated MIF-2 expression in adipocytes. Mif gene deletion polarized adipose tissue macrophages (ATM) toward an anti-inflammatory phenotype while Mif-2 gene knockout drove ATMs toward a pro-inflammatory phenotype and Mif-deficiency was found to increase fibroblast viability. Additionally, we observed the same differential regulation of these two MIF family proteins in human adipose tissue in septic vs healthy patients. Taken together, these data suggest an inverse relationship between adipocyte MIF and MIF-2 expression during systemic inflammation, with the downregulation of MIF-2 in fat tissue potentially increasing pro-inflammatory macrophage polarization to further drive adipose inflammation.

SUBMITTER: Kim BS

PROVIDER: S-EPMC7060131 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

Kim Bong-Sung BS Tilstam Pathricia V PV Arnke Kevin K Leng Lin L Ruhl Tim T Piecychna Marta M Schulte Wibke W Sauler Maor M Frueh Florian S FS Storti Gabriele G Lindenblatt Nicole N Giovanoli Pietro P Pallua Norbert N Bernhagen Jürgen J Bucala Richard R

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200121 3

Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT/MIF-2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF-2 levels were increased in the peritoneal fluid of LPS-challenged wild-type mice, yet, in visceral WAT, ...[more]

PMID: 31961019

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Project description:BackgroundPorcine adipose tissue expresses orosomucoid (ORM1) mRNA, a protein with anti-inflammatory and immunomodulatory properties. Previous research has demonstrated that porcine ORM1 can reduce insulin stimulated glucose metabolism in porcine adipose tissue in vitro. The present study was designed to examine the preweaning ontogeny of ORM1 mRNA abundance in porcine subcutaneous adipose and to determine if ORM1 can regulate mRNA abundance of inflammatory cytokines that contribute to insulin resistance in primary cultures derived from neonatal porcine subcutaneous adipose tissue. Cultures were differentiated in vitro and subsequently the adipocyte containing cultures were incubated for 24 h with 0-5000 ng porcine ORM1/mL medium. Cultures were then harvested, total RNA extracted for use in reverse transcription and the mRNA abundance of cytokine mRNA quantified by real-time PCR.ResultsORM1 mRNA abundance within neonatal adipose tissue does not change from d 1 to d 21 of age and is a very small fraction relative to liver mRNA abundance. The ORM1 mRNA level in porcine adipocytes and stromal-vascular cells are similar (P > 0.05). Treatment with ORM1 did not affect TNFα (tumor necrosis factor α) mRNA level (P > 0.05), while interleukin 6 (IL6) mRNA abundance was reduced 32 % at 1,000 ng ORM1/mL (P < 0.01). However, TNFα protein content in the cell culture media was reduced by ORM1 treatment (5,000 ng/mL, P < 0.05), whereas ORM1 had no detectable effect on the media content of IL6 (P > 0.05). The reduction of macrophage migration inhibitory factor (MIF) mRNA abundance by ORM1 was dose dependent (P < 0.01). Monocyte chemotactic protein (MCP) mRNA level was reduced 27 % by 1,000 ng ORM1/mL (P < 0.05).ConclusionsThe data suggest that ORM1 has limited effects TNFα, IL6, MIF or MCP expression at the concentrations tested. Secondly, these cytokines do not appear to contribute to the reported insulin resistance induced by ORM1 in porcine adipose tissue in vitro as an increase in the abundance of these inflammatory cytokines would be predicted during an insulin resistant state.

Dataset Information

Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

Publications

Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia.

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