α-Melanocyte-stimulating Hormone Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α Production in Leukocytes by Modulating Protein Kinase A, p38 Kinase, and Nuclear Factor κB Signaling Pathways

Abstract

The neuropeptide ␣-melanocyte-stimulating hormone (␣-MSH) inhibits inflammation by down-regulating the expression of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) in leukocytes via stimulation of ␣-MSH cell surface receptors. However, the signaling mechanism of ␣-MSH action has not yet been clearly elucidated. Here, we have investigated signaling pathways by which ␣-MSH inhibits lipopolysaccharide (LPS)-induced TNF-␣ production in leukocytes such as THP-1 cells. We focused on the possible roles of protein kinase A (PKA), p38 kinase, and nuclear factor B (NF B) signaling. In THP-1 cells, LPS is known to activate p38 kinase, which in turn activates NF B to induce TNF-␣ production. We found that pretreatment of cells with ␣-MSH blocked LPS-induced p38 kinase and NF B activation as well as TNF-␣ production. This response was proportional to ␣-MSH receptor expression levels, and addition of an ␣-MSH receptor antagonist abolished the inhibitory effects. In addition, ␣-MSH treatment activated PKA, and PKA inhibition abrogated the inhibitory effects of ␣-MSH on p38 kinase activation, NF B activation, and TNF-␣ production. Taken together, our results indicate that stimulation of PKA by ␣-MSH causes inhibition of LPS-induced activation of p38 kinase and NF B to block TNF-␣ production.

Central Neurotranspeptide, Alpha-Melanocyte-Stimulating Hormone (.ALPHA.-MSH) is Upregulated in Patients with Congestive Heart Failure

“…In human diseases, the relationship between concentrations of α-MSH and disease progression in HIV-infection was explored in a prospective study (19). Circulating α-MSH returned to normal levels in patients with sepsis syndrome who recovered and it remained low in those who died (20) As previously reported (23,24), the response to α-MSH was biphasic in inhibitory effects on LPS-induced TNF-α production. One of the possibilities of the reason may be that α-MSH could modulate both inflammatory and antiinflammatory responses regulating intracellular peroxide levels and glutathione peroxidase activity, and an excess dose of α-MSH could break the immunobalance (23).…”

The immunomodulating neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages

“…The treatment of LPS-stimulated macrophages with α-MSH prevents the translocation of NF-κB from the cytoplasm to the nucleus resulting from a block in IκB degradation (Deng et al, 2004). In addition, the α-MSH-treated macrophages have deactivated p38 (Yoon et al, 2003). These findings suggested that there must be a more proximal inhibition of the LPS-induced intracellular signaling cascade.…”

“…The most predominate melanocortin receptor on macrophages and dendritic cells is MC1r (Neumann Andersen et al, 2001), although message for MC3r and MC5r can be detected (Taherzadeh et al, 1999). The engagement of α-MSH with MC1r elevates cAMP levels in the macrophages and activates a cAMP-dependent protein kinase A (PKA; Yoon et al, 2003). The activation of PKA is linked to the inhibition of LPS-activated p38 MAPK and NF-κB.…”

“…The treatment of mice with α-MSH at the time of haptensensitization causes antigen presenting cells (APC) to prime immunity devoid of a hypersensitivity response (Grabbe et al, 1996). Through melanocortin 1 and melanocortin 3 receptors on macrophages, α-MSH suppresses endotoxin activation of p38 MAPK and NF-κB (Getting et al, 2003;Ichiyama et al, 1999;Yoon et al, 2003). There is a constitutive level of α-MSH in various body tissues and fluids, and in response to a systemic inflammatory response there is an elevation of its concentration in blood (Holdeman et al, 1985;Taylor and Streilein, 1996;Taylor et al, 1992).…”

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (α-MSH) therapy

“…The neuropeptide suppresses the pro-inflammatory activity of both innate and adaptive immunity. In macrophages through the melanocortin 1 and 3 receptors, α-MSH suppresses the activation of NF-κB and p38MAP-kinase by IL-1, TNF-α, and endotoxin Manna and Aggarwal, 1998;Taherzadeh et al, 1999;Yoon et al, 2003). The α-MSH suppression of endotoxin mediated inflammation is the result of blocking toll like receptor-4 (TLR4) signaling in macrophages either through suppression of CD14 expression or by translocation of IRAK-M to the endotoxin-engaged TLR4 intracellular complex (Sarkar et al, 2003;Taylor, 2005).…”