Inhibition of peripheral NF-kappa B activation by central action of alpha-melanocyte-stimulating hormone

With the rise in the field of neuroimmunomodulation research, there is incr eased recognition of the influence of the nervous system and neuropeptides in peripheral disease. The neuropeptide alpha-melanocyte-stimulating hormon e (alpha-MSH) is a neuroimmunomodulatory agent that modulates production of proinflammatory cytokines and inhibits peripheral inflammation via actions on CNS receptors. We examined whether central alpha-MSH operates by inhibi ting activation of the nuclear factor kappa B (NF-kappa B) that is essentia l to the expression of proinflammatory cytokines and development of inflamm ation in the periphery. Electrophoretic mobility shift assays of nuclear ex tracts from the murine foot pad injected with TNF-alpha demonstrated that c entrally administered alpha-MSH does inhibit NF-kappa B activation. Western blot analysis revealed that this inhibition was linked to central alpha-MS H-induced preservation of expression of I kappa B alpha protein in the peri pheral tissue. The NF-kappa B and I kappa B alpha effects were inhibited in mice with spinal cord transection. Intraperitoneal (ip) injection of the n onspecific beta-adrenergic receptor blocker propranolol, and of a specific beta(2)-adrenergic receptor antagonist, likewise prevented these effects of central alpha-MSH; blockade of cholinergic, alpha-adrenergic, or beta(1)-a drenergic receptors did not. Centrally administered alpha-MSH inhibited per ipheral NF-kappa B activation and I kappa B alpha degradation even in mice with nonfunctional melanocortin 1 receptors (MC1R). These findings indicate that alpha-MSH can act centrally to inhibit NF-kappa B activation in perip heral acute inflammation via a descending neural pathway. The pathway invol ves beta(2)-adrenergic receptors, but does not require activation of MC1R w ithin the brain. (C) 1999 Elsevier Science B.V. All rights reserved.