Melanocortins induce interleukin 6 gene expression and secretion through melanocortin receptors 2 and 5 in 3T3-L1 adipocytes

Abstract

Interleukin 6 (IL6) is a pleiotropic cytokine that not only affects the immune system, but also plays an active role in many physiological events in various organs. Notably, 35% of systemic IL6 originates from adipose tissues under noninflammatory conditions. Here, we describe a previously unknown function of melanocortins in regulating Il6 gene expression and production in 3T3-L1 adipocytes through membrane receptors which are called melanocortin receptors (MCRs). Of the five MCRs that have been cloned, MC2R and MC5R are expressed during adipocyte differentiation. α-Melanocyte-stimulating hormone (α-MSH) or ACTH treatment of 3T3-L1 adipocytes induces Il6 gene expression and production in a time- and concentration-dependent manner via various signaling pathways including the protein kinase A, p38 mitogen-activated protein kinase, cJun N-terminal kinase, and IκB kinase pathways. Specific inhibition of MC2R and MC5R expression with short interfering Mc2r and Mc5r RNAs significantly attenuated the α-MSH-induced increase of intracellular cAMP and both the level of Il6 mRNA and secretion of IL6 in 3T3-L1 adipocytes. Finally, when injected into mouse tail vein, α-MSH dramatically increased the Il6 transcript levels in epididymal fat pads. These results suggest that α-MSH in addition to ACTH may function as a regulator of inflammation by regulating cytokine production.

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage

“…88–90 However, this effect is confounded by conflicting data indicating that α-MSH increases IL-6 expression. 91 Although ghrelin is usually thought of as an upstream regulator of the melanocortin pathway, there is some evidence that α-MSH can directly affect the release of ghrelin (Figure 4I). 92 It is therefore unclear if the current increase in ghrelin after CJL-1-87 treatment is a direct pharmacological effect or an effect of the decreased food intake.…”

Developing an anti-Campylobacter jejunivaccine

“…The bacterial pentapeptide is present in 11 human proteins, all of which play fundamental roles in crucial cellular processes, such as tight junction-specific obliteration of the intercellular space (claudin-10), structural adhesion of the skin epithelium to the underlying mesenchyme (FREM3), sperm motility (Q7RTX7), and sensory activities (SCNBA) ( Table 2). (44)(45)(46)(47)(48)(49)(50)(51) Therefore, using the entire CDT toxin, or even one of the three toxin domains, might cause autoimmune collateral crossreactions because of the high number of pentapeptide matches with the human proteome.…”

“…This receptor is a possible mediator of the immunomodulation properties of melanocortins. (46) Q32MA7: S4A5. Solute carrier family 4 member 5.…”

Melanocortin receptors and their accessory proteins

“…Human adipose tissue samples have been shown to express MC1R and low levels of MC4R and MC5R (Hoch et al, 2007). Treatment of 3T3L1 cells with melanocortin ligands promotes lipolysis and cytokine production in vitro, however, this observation has not been replicated in human mesenchymal cell derived adipocytes (Hoch et al, 2008;Jun et al, 2010;Moller et al, 2011).…”