Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis

Barry G Arnason, Regina Berkovich, Anna Catania, Robert P Lisak, Mone Zaidi, Barry G Arnason, Regina Berkovich, Anna Catania, Robert P Lisak, Mone Zaidi

Abstract

The therapeutic benefits of adrenocorticotropic hormone in multiple sclerosis are usually ascribed to its corticotropic actions. Evidence is presented that adrenocorticotropic hormone, approved for multiple sclerosis relapses, acts via corticosteroid-independent melanocortin pathways to engender down-modulating actions on immune-system cells and the cytokines they synthesize. Immune response-dampening effects are also brought about by agent-induced neurotransmitters that inhibit immunocytes. The likelihood that adrenocorticotropic hormone promotes microglial quiescence and counteracts glucocorticoid-mediated bone resorption is discussed.

Conflict of interest statement

Conflict of interest: BGA has served as a consultant within the past 12 months to Acorda, Bayer, Novartis, Questcor and sanofi-aventis. He is an investigator in a clinical trial sponsored by sanofi-aventis, from which the University of Chicago receives salary recovery. He is the recipient of a research grant from Questcor, from which there is no salary recovery.

RB is a speaker and consultant for Acorda, Bayer, Biogen Idec, Questcor and Teva Pharmaceuticals.

AC is a member of the Questcor Acthar MOA Advisory Board.

RPL has served as a consultant within the past 12 months to Avanir, Geron, Questcor, sanofi-aventis, Teva Neuroscience and Teva Pharmaceuticals. He is an investigator in clinical trials sponsored by Biogen/Idec, Genzyme, Novartis and Teva Neuroscience, from which Wayne State University receives salary recovery. He is a recipient of research grants from Avanir, Questcor, Teva Neuroscience and Teva Pharmaceuticals, from which Wayne State University receives salary recovery.

MZ is supported by the US National Institutes of Health (RO1 AG023176, DK 0804590 and AG 040132). MZ discloses participating as a speaker/consultant to Amgen, Genentech/Roche, Questcor and Warner Chilcott within the past 12 months. MZ is also inventor on Mount Sinai School of Medicine’s patent applications relating to the use of FSH and TSH in disorders of bone remodeling, and will be receiving royalties should these patents mature.

Figures

Figure 1a.
Figure 1a.
Melanocortin peptides (shaded boxes) derived from POMC. ACTH: adrenocorticotropic hormone; CLIP: corticotropin-like intermediate lobe peptide; MSH: melanocyte-stimulating hormone; POMC: pro-opiomelanocortin, Reprinted with permission from: Catania A, et al. Pharmacol Rev 2004; 56: 1-29.
Figure 1b.
Figure 1b.
Melanocortin inhibition of NF-kB activation in immunocytes. NF-lB is inactive in the cytoplasm, bound to IlB. Cytokines, chemokines, endotoxins and pathogens cause IlB phosphorylation and degradation. Free NF-lB translocates to the nucleus to trigger transcription of proinflammatory molecules. MCR activation by melanocortins inhibits IlBa phosphorylation and NF-lB nuclear translocation. MCR: melanocortin receptor; NF-lB: nuclear factor-kappaB. Reprinted with permission from: Catania A. J Leukoc Biol 2007; 81: 383–392.
Figure 1c.
Figure 1c.
ACTH/melanocortin anti-inflammatory circuits. Pathogens, endotoxins (LPS), cytokines and other stressors enhance hypothalamic secretion of corticotropin-releasing hormone (CRH), which induces POMC processing and ACTH release from anterior pituitary. Circulating ACTH activates adrenal MC2Rs and promotes a systemic glucocorticoid-mediated anti-inflammatory response. Additionally, ACTH activates MCR subtypes within the brain (MC3R and MC4R) and elsewhere (MC1R, MC3R and MC5R). ACTH exerts glucocorticoid-independent anti-inflammatory actions at sites of inflammation and via central neurogenic pathways. LPS and cytokines induce POMC processing in extrapituitary cells, including brain cells, immunocytes, endothelial cells and keratinocytes (not discussed herein). The main product is α-MSH that likewise exerts potent anti-inflammatory actions. ACTH: adrenocorticotropic hormone; LPS: lipopolysaccharide; MCR: melanocortin receptor; MSH: melanocyte-stimulating hormone; POMC: pro-opiomelanocortin. Reprinted with permission from: Catania A. J Leukoc Biol 2007; 81: 383–392.

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