Molecules in focus
Macrophage inflammatory protein-1

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Abstract

Macrophage inflammatory protein (MIP)-1α was identified 15 years ago as the first of now four members of the MIP-1 CC chemokine subfamily. These proteins termed CCL3 (MIP-1α), CCL4 (MIP-1β), CCL9/10 (MIP-1δ), and CCL15 (MIP-1γ) according to the revised nomenclature for chemokines are produced by many cells, particularly macrophages, dendritic cells, and lymphocytes. MIP-1 proteins, which act via G-protein-coupled cell surface receptors (CCR1, 3, 5), e.g. expressed by lymphocytes and monocytes/macrophages (MΦ), are best known for their chemotactic and proinflammatory effects but can also promote homoeostasis. The encouraging results of preclinical studies in murine models of inflammation, i.e. asthma, arthritis, or multiple sclerosis, have led to the development of potent CCR3 and 5 antagonists, some of which are currently being tested in first clinical trials.

Introduction

Two recent and important findings have led to a renewed interest in MIP-1 proteins (MIP-1α, β, γ, δ), highly related ligands and activators of CC chemokine receptors (mainly CCR1, 3, and 5): (1) the MΦ effector chemokines CCL3 and CCL4, which are produced and secreted by activated MΦ to attract other proinflammatory cells, are also crucial in recruiting MΦ themselves to sites of inflammation; and (2) CCL3 can potently inhibit the MΦ uptake of HIV-1 via CCR5 ligation.

Section snippets

Structure

MIP-1 proteins are small (8–10 kDa), structurally related, inducible, secreted, and proinflammatory chemokines of the CC subfamily, one of four chemokine groups (i.e. CXC, C, CC, and CX3C) as defined by their primary structure. In mice and humans the MIP-1 family members CCL3 (mice: MIP-1α, human: MIP-1α/LD78α) and CCL4 (mice and human: MIP-1β) are encoded by genes consisting of three exons and two introns located on chromosomes 11 and 17, respectively (Fig. 1, Table 1). The highly related

Synthesis and degradation

The genes for CCL3 and CCL4 are inducible in most mature hematopoietic cells. Cells that are directly involved in eliciting immune responses, i.e. MΦ, T- and B-lymphocytes, neutrophils, dendritic cells, mast cells and NK cells, can produce large amounts of MIP-1 (up to several nanograms/106 cells). Platelets, osteoblasts, astrocytes and microglia, epithelial cells, fibroblasts and other cells produce less CCL3/4 upon stimulation. Generally, the synthesis (and release) of CCL3/4 requires cell

Biological function

MIP-1 proteins mediate their biological effects by binding to cell surface CC chemokine receptors (3×104 to 5×105 receptors per cell), which belong to the G-protein-coupled receptor superfamily (Table 1). Receptor binding involves high affinity interactions and a subsequent cascade of intracellular events that rapidly leads to a wide range of target cell functions including chemotaxis, degranulation, phagocytosis, and mediator synthesis. Signal transduction events are initiated by the G-protein

Possible medical applications

During the past years rapid advances have been made in the identification and characterization of MIP-1 receptor antagonists (Horuk, 2003). Potent, orally bioavailable, synthetic small molecule antagonists of both CCR1 and CCR5 are currently tested in phase I/II clinical trials (Carter, 2002). Their development is driven by two goals: (1) to inhibit the proinflammatory effects of MIP-1 proteins and other ligands of CCR1 and CCR5 that have been shown to contribute to the pathogenesis of

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