Elsevier

Journal of Neuroimmunology

Volume 99, Issue 2, 29 October 1999, Pages 211-217
Journal of Neuroimmunology

Inhibition of peripheral NF-κB activation by central action of α-melanocyte-stimulating hormone

https://doi.org/10.1016/S0165-5728(99)00122-8Get rights and content

Abstract

With the rise in the field of neuroimmunomodulation research, there is increased recognition of the influence of the nervous system and neuropeptides in peripheral disease. The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a neuroimmunomodulatory agent that modulates production of proinflammatory cytokines and inhibits peripheral inflammation via actions on CNS receptors. We examined whether central α-MSH operates by inhibiting activation of the nuclear factor kappa B (NF-κB) that is essential to the expression of proinflammatory cytokines and development of inflammation in the periphery. Electrophoretic mobility shift assays of nuclear extracts from the murine foot pad injected with TNF-α demonstrated that centrally administered α-MSH does inhibit NF-κB activation. Western blot analysis revealed that this inhibition was linked to central α-MSH-induced preservation of expression of IκBα protein in the peripheral tissue. The NF-κB and IκBα effects were inhibited in mice with spinal cord transection. Intraperitoneal (ip) injection of the nonspecific β-adrenergic receptor blocker propranolol, and of a specific β2-adrenergic receptor antagonist, likewise prevented these effects of central α-MSH; blockade of cholinergic, α-adrenergic, or β1-adrenergic receptors did not. Centrally administered α-MSH inhibited peripheral NF-κB activation and IκBα degradation even in mice with nonfunctional melanocortin 1 receptors (MC1R). These findings indicate that α-MSH can act centrally to inhibit NF-κB activation in peripheral acute inflammation via a descending neural pathway. The pathway involves β2-adrenergic receptors, but does not require activation of MC1R within the brain.

Introduction

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) exerts anti-inflammatory effects through inhibition of production and action of proinflammatory cytokines (Lipton and Catania, 1997, Lipton and Catania, 1998). α-MSH is a pro-opiomelanocortin derivative which shares the 1–13 amino acid sequence with adrenocorticotropic hormone; this peptide occurs in the pituitary, brain, skin, circulation, and other sites (Catania and Lipton, 1993). α-MSH is a melanocortin and five melanocortin receptor subtypes have been identified (MC1R through MC5R) (Chhajlani and Wikberg, 1992; Mountjoy et al., 1992; Gantz et al., 1993a, Gantz et al., 1993b; Barrett et al., 1994). It is thought that the local anti-inflammatory effects of α-MSH are mediated through MC1R on neutrophils, monocyte/macrophages, and on brain cells (Catania et al., 1996; Rajora et al., 1996, Rajora et al., 1997; Wong et al., 1997). In addition, α-MSH exerts an anti-inflammatory effect on peripheral inflammation through descending neural pathways (Lipton et al., 1991; Ceriani et al., 1994; Macaluso et al., 1994). It has not been established which receptors mediate the central α-MSH-induced inhibition of peripheral inflammation.

Nuclear factor kappa B (NF-κB) is a pivotal transcription factor for genes that encode proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-α (Collart et al., 1990; Libermann and Baltimore, 1990; Hiscott et al., 1993; Matsusaka et al., 1993; Kunsch et al., 1994; Roulston et al., 1995). The primary form of NF-κB consists of a heterodimer of p50 and p65 that is bound by members of the IκB family, including IκBα, in cytoplasm (Baeuerle and Henkel, 1994; Baldwin, 1996). NF-κB activation requires degradation of IκBα protein (Grimm and Baeuerle, 1993; Henkel et al., 1993). Phosphorylation of IκBα by drugs, cytokines, bacterial products, and viruses leads to IκBα degradation, translocation of NF-κB to the nucleus, and transcription of proinflammatory cytokine genes (Kumar et al., 1994; Brown et al., 1995). α-MSH inhibits NF-κB activation and IκBα degradation in cultured cells (Manna and Aggarwal, 1998). We tested the hypothesis that central α-MSH modulates peripheral acute inflammation by inhibiting NF-κB activation through descending neural pathways stemming from MC1R within the brain.

Section snippets

Animals

These experiments were approved by the local Internal Review Board for Animal Research. Male C57BL/6 mice (Simonsen Laboratories, Gilroy, CA) were housed in a 24±1°C environment in groups not exceeding five animals per cage (28×18×13 cm3). They were allowed to acclimatize to standard lighting and temperature conditions with food and water freely available before experiments began.

Mice with nonfunctional MC1R (MC-1re/MC-1re) originated from stock bred by Dr. G. S. Barsh of Stanford University

Inhibition by centrally administered α-MSH of NF-κB activation in the periphery

EMSA of nuclear extracts from foot pads injected with TNF-α demonstrated NF-κB activation (Fig. 1). NF-κB activation was observed throughout the 3-h test period in the TNF-α-treated foot pads of mice given central injection of saline. The gel shift bands of nuclear extracts from the foot pads injected with TNF-α were reduced by centrally administered α-MSH (Fig. 1). Densitometry showed an inhibition of approximately 40%. Specificity of the NF-κB consensus oligonucleotide probe was confirmed in

Discussion

Inflammation is characteristic in many diseases of the periphery including arthritis, inflammatory bowel disease, asthma, and vascular disease. Therapy for these disorders has not progressed rapidly and perhaps a new avenue for control via agents that act on the CNS will be beneficial. Our results suggest that targeting CNS α-MSH receptors could improve peripheral inflammation.

Our data demonstrate that centrally administered α-MSH inhibits NF-κB activation and IκBα degradation in peripheral

Summary

Our data indicate that α-MSH injected centrally can restrict IκBα degradation and subsequent NF-κB activation in peripheral acute inflammation. Spinal cord transections revealed that an intact descending neural pathway is necessary for centrally administered α-MSH to exert these effects. Pharmacological studies indicate that β2-adrenoreceptors in the periphery are likewise important in the anti-inflammatory pathway activated by centrally administered α-MSH. Experiments on MC-1re/MC-1re mice

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