Endocrine Modulation of Inflammation: The Role of Adrenocorticotropic Hormone and Cortisol

The melanocortin system, derived from pro-opiomelanocortin processing, represents a crucial neuroendocrine-immune interface that regulates inflammatory and metabolic pathways. Through its 5 melanocortin receptors (MCRs), MCR1 to MCR5, this system exerts widespread endocrine, paracrine, and autocrine functions across the central nervous system, skin, adipose tissue, bone, and immune cells. Activation of melanocortin signaling produces potent anti-inflammatory effects by modulating cytokine release, leukocyte trafficking, and transcriptional control of proinflammatory mediators. Adrenocorticotropic hormone (ACTH), via the hypothalamic-pituitary-adrenal axis and direct interaction with MCR2, stimulates both cortisol synthesis and mediates steroid-independent immunomodulation in extra-adrenal tissues. It should be taken into account that ACTH is the only ligand for MCR2 inducing steroidogenesis, cell proliferation and anti-inflammatory effects. Synthetic and natural ACTH formulations, such as repository corticotropin injection (Acthar® Gel) and Purified Cortrophin Gel, have demonstrated clinical benefit in refractory inflammatory diseases, as their efficacy may extend beyond classic glucocorticoid pathways. Recent preclinical studies of selective MCR agonists, including MCR1-targeted compounds like dersimelagon, highlight novel therapeutic possibilities for autoimmune and fibrotic disorders. Understanding the dual steroidogenic and nonsteroidogenic actions of melanocortins provides a framework for developing targeted therapies with improved safety profiles compared with conventional glucocorticoids.