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Article

Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation

Divisions of Internal Medicine (A.C., G.C.) and Liver Transplantation (S.G.), Ospedale Maggiore di Milano, Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy; and Zengen, Inc. (J.M.L.), Woodland Hills, California

Abstract

I. Introduction

II. Proopiomelanocortin Gene, Gene Expression, and Post-Translational Processing

A. Proopiomelanocortin Gene

B. Proopiomelanocortin Gene Expression

C. Post-Translational Processing of Proopiomelanocortin

D. Melanocortin Peptides

III. Melanocortin Receptors and Their Endogenous Antagonists

A. MC1 Receptor

B. MC2 Receptor

C. MC3 Receptor

D. MC4 Receptor

E. MC5 Receptor

F. Agouti and Agouti Gene-Related Protein

IV. Intracellular Signaling

V. Structure-Activity Relationship of Melanocortin Peptides

VI. Mechanism of the Anti-Inflammatory Action of Melanocortins

A. Receptor Subtypes Involved in the Anti-Inflammatory Effects of Melanocortins

B. Influence of Melanocortins on Nuclear Factor-{kappa}B-Mediated Transcription

C. Melanocortins Modulate Production of Chemical Mediators of Inflammation

1. Effects in Vitro.

2. Effects in Vivo.

D. Central Control of Peripheral Inflammation

VII. Antipyretic Influences of Melanocortins

VIII. Changes in Endogenous {alpha}-Melanocyte-Stimulating Hormone in Inflammatory Disorders

IX. Potential Therapeutic Targets Based on Preclinical Studies in Inflammatory Disorders

A. Acute Inflammation

1. Allergic Inflammation.

2. Autoimmune Uveoretinitis.

3. Gouty Arthritis.

B. Chronic Inflammatory Diseases

1. Rheumatoid Arthritis.

2. Inflammatory Bowel Diseases.

C. Inflammation within the Brain and Neurodegenerative Disorders

D. Peripheral Neuropathies

E. Systemic Host Reactions

1. Septic Shock.

2. Systemic Vasculitis.

3. Acute Respiratory Distress Syndrome.

4. Hemorrhagic Shock.

F. Ischemia and Reperfusion Injury

G. Organ Transplantation

H. Infections

X. Advantages over Currently Used Anti-Inflammatory Drugs and Potential Disadvantages

Adrenocorticotropic hormone and -, -, and -melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor B to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.