- Email: [email protected]
Macrophage inflammatory protein-1
The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Molecules in focus
Macrophage inflammatory protein-1 M. Maurer∗ , E. von Stebut Department of Dermatology, University of Mainz, Langenbeckstr. 1, Mainz 55101, Germany Received 5 September 2003; received in revised form 27 October 2003; accepted 27 October 2003
Abstract Macrophage inflammatory protein (MIP)-1␣ was identified 15 years ago as the first of now four members of the MIP-1 CC chemokine subfamily. These proteins termed CCL3 (MIP-1␣), CCL4 (MIP-1), CCL9/10 (MIP-1␦), and CCL15 (MIP-1␥) 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 (M), 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. © 2003 Elsevier Ltd. All rights reserved. Keywords: Chemokine; MIP-1; CCL3; CCL4; CCR5
1. Introduction
2. Structure
Two recent and important findings have led to a renewed interest in MIP-1 proteins (MIP-1␣, , ␥, ␦), highly related ligands and activators of CC chemokine receptors (mainly CCR1, 3, and 5): (1) the M effector chemokines CCL3 and CCL4, which are produced and secreted by activated M to attract other proinflammatory cells, are also crucial in recruiting M themselves to sites of inflammation; and (2) CCL3 can potently inhibit the M uptake of HIV-1 via CCR5 ligation.
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-1␣, human: MIP-1␣/LD78␣) and CCL4 (mice and human: MIP-1) 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 murine and human CCL3 and CCL4 proteins are synthesized as 92 aa precursors. Mature secreted proteins (69–70 aa) are generated by peptidases that cleave hydrophobic signal peptides, most of which have recently been identified (Menten, Wuyts, & von Damme, 2002). Other MIP-1 proteins such as CCL3L1/MIP-1␣/LD78, CCL15/MIP-1␦ in humans or CCL9/10/MIP-1␥ in mice are not as well
∗ Corresponding author. Tel.: +49-6131-17-5293; fax: +49-6131-17-6614. E-mail address: [email protected] (M. Maurer).
1357-2725/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2003.10.019
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
1883
Fig. 1. Gene and protein structures of MIP-1. (A) Comparison of human and murine MIP-1␣/ genes. Horizontal lines represent intron sequences, boxes represent exon sequences: gray = untranslated leader sequences, green = translated leader sequences, red = translated mature protein sequences. Numbers indicate the lengths of segments. (B) Comparison of primary structures of mature MIP-1 proteins.
characterized in terms of gene and protein structure (Table 1). At physiologically relevant concentrations, i.e. <100 ng/ml, CCL3 is found only in its monomeric form, whereas dynamic and reversible aggregation occurs at higher concentrations. While self-aggregation does not influence MIP-1 bioactivity, binding to proteoglycans such as heparin appears to enhance it (Menten et al., 2002).
3. 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. M, Tand 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 activation, although low level baseline expression can sometimes be detected in unstimulated cells, e.g. in neutrophils. MIP-1 production can be induced by various proinflammatory agents/cytokines including LPS, substance P, viral infection, TNF␣, IFN␥, IL-1␣/ and others, whereas
treatment with IL-4, IL-10, dexamethason or other anti-inflammatory signals is known to downregulate MIP-1 expression. There is only limited information on the degradation and biological half life of MIP-1. Recent studies suggest that MIP-1 activity may be limited by proteases, e.g. cathepsin D, as both CCL3 and CCL4 are cleaved and inactivated by this enzyme (Wolf et al., 2003). On the other hand, proteolytic truncation of MIP-1 proteins, i.e. CCL3L1 (MIP-1␣/LD78), CCL4, and CCL15, can also increase their bioactivity (Proost et al., 2000; Lee et al., 2002; Guan, Wang, Rodriguez, & Norcross, 2002).
4. 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 complex leading to its
a
Mo: monocytes, N: neutrophils, Eo: eosinophils, T: T-cells, Baso: basophils, DC: dendritic cells, ?: not known.
CCL3, RANTES, MCP-2, HCC-1, M-tropic HIV-1 CCL3, RANTES, MCP-2, HCC-1, M-tropic HIV-1 CCL15, RANTES, MPIF-1, MCP-2,3, HCC-1/4 CCL15, RANTES, MPIF-1, MCP-2,3, HCC-1/4 RANTES, MCP-2/3, Eotaxin(-2/3), MEC (Mo > T, DC) (Mo > T, DC) (Mo > N > Eo) (Mo = N > Eo) (Eo > Baso, T) CCR5 CCR5 CCR1 CCR1 CCR3 MIP-1 11 (654 bp) MIP-1␥ 11 (1255 bp) ? ? 17 (960 bp) 17 (696 bp) ? 17 (955–1392 bp) MIP-1 ? MIP-1␦/Lkn-1 CCL4 CCL9/10 CCL15
MIP-1␣ 11 (764 bp) MIP-1␣/LD78␣ (MIP-1␣/LD78) CCL3 (CCL3L1)
Ligand Chromosome (transcript size in base pairs (bp)) Ligand
Chromosome (transcript size in base pairs (bp))
Receptor (expression by) Mouse Human
MIP-1 chemokine subfamily
Table 1 MIP-1 proteins and their receptorsa
17 (776 bp)
CCR1 (Mo, T > N > Eo) CCL15, RANTES, MPIF-1, MCP-2,3, HCC-1/4
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Selected alternative ligands
1884
dissociation into G␣ and G␥ subunits (Proudfoot, Power, Rommel, & Wells, 2003). G␣ induces phosphoinositide 3-kinase (PI3K) pathway activation, and G␥ subunits activate phospholipase C and induce Ca2+ influx resulting in protein kinase C isoform activation. It has also been shown that MAP kinases as well as the JAK/STAT signaling cascade are involved. The exact downstream events induced by CCL3 and CCL4 remain to be characterized. MIP-1 receptors, as all CCRs, bind several different chemokines, whereas MIP-1 proteins exhibit (relatively) high receptor specificity (Table 1). MIP-1 family members orchestrate acute and chronic inflammatory host responses at sites of injury or infection mainly by recruiting proinflammatory cells (compare Table 1). They are crucial for T-cell chemotaxis from the circulation to inflamed tissue and also play an important role in the regulation of transendothelial migration of monocytes, dendritic cells, and NK cells. Neutrophils and eosinophils are less responsive to the chemotactic effects of MIP-1: CCL3 can only recruit IFN␥-activated neutrophils and only small subpopulations of CCR1 expressing eosinophils. CCR1, CCR3, and CCR5 activation by MIP-1 also leads to Ca2+ release, upregulation of activation markers and release of proinflammatory mediators such as LTC4 , arachidonic acid or histamine. In addition, MIP-1 proteins can regulate immune responses by modulating Th-differentiation. CCL3 and its receptor CCR5 promote Th1 skewing, e.g. CCR5-deficient mice display Th2-skewed cytokine profiles (Andres et al., 2000), whereas Th2 cells mainly express CCR2 and CCR4 (Luther & Cyster, 2001). Thus, it is not surprising that MIP-1 proteins are key players in the pathogenesis of many inflammatory conditions and diseases (Fig. 2) including asthma, granuloma formation, wound healing, arthritis, multiple sclerosis (murine EAE model), pneumonia, and psoriasis (Murdoch & Finn, 2000). For example, CCL3 and CCL4 released from neutrophils that are recruited to sites of skin injury by mast cell-derived TNF␣ were found to be crucial mediators for M influx in a murine model of cutaneous granuloma formation (von Stebut, Metz, Milon, Knop, & Maurer, 2003). CCL3 also appears to be the critical M chemoattractant in cutaneous wound repair, where it promotes healing (DiPietro et al., 1998), and it
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Fig. 2. Selection of human diseases promoted by MIP-1 proteins.
contributes to antigen-dependent basophil chemotaxis, histamine release and the development of eosinophilia in a model of allergic asthma (Venge, Lampinen, Hakansson, Rak, & Venge, 1996). MIP-1 proteins can also promote health by inducing inflammatory responses against infectious pathogens such as viruses, e.g. influenza (Menten et al., 2002) or parasites (Aliberti et al., 2000). For example, in Toxoplasma gondii infection CCL3 and CCL4 (and CCL5/RANTES) increase IL-12 release from dendritic cells by binding to CCR5, which results in enhanced Th1 immunity and clearance of the parasite (Venge et al., 1996). On the other hand, the MIP-1 receptors CCR3 and CCR5 promote HIV-1 infection as they are important co-receptors for M-tropic HIV-1 viruses on CD4+ target cells (Horuk, 2003). In summary, MIP-1 plays a key role in the induction and modulation of inflammatory responses, i.e. in the context of autoimmune reactions and host defense responses (Fig. 2). In addition, MIP-1 proteins also regulate various aspects of tissue homeostasis. In the interest of space, these important physiological MIP-1 functions, e.g. in thymic and stem cell development, angiogenesis, and tumor biology, which are discussed in excellent recent reviews (Menten et al., 2002; Homey, Muller, & Zlotnik, 2002), are not considered here.
5. Possible medical applications During the past years rapid advances have been made in the identification and characterization of
1885
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 autoimmune and other inflammatory diseases (e.g. multiple sclerosis, organ transplant rejection, rheumatoid arthritis, asthma); (2) to identify specific and potent virus uptake inhibitors that block HIV-1 entry via its major co-receptor CCR5 (Horuk, 2003). References Aliberti, J., Reis e Sousa, C., Schito, M., Hieny, S., Wells, T., Huffnagle, G. B., & Sher, A. (2000). CCR5 provides a signal for microbial induced production of IL-12 by CD8 alpha+ dendritic cells. Natural Immunology, 1, 83–87. Andres, P. G., Beck, P. L., Mizoguchi, E., Mizoguchi, A., Bhan, A. K., Dawson, T., Kuziel, W. A., Maeda, N., MacDermott, R. P., Podolsky, D. K., & Reinecker, H. C. (2000). Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: Lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. Journal on Immunology, 164, 6303–6312. Carter, P. H. (2002). Chemokine receptor antagonism as an approach to anti-inflammatory therapy: Just right or plain wrong? Current Opinion in Chemical Biology, 6, 510–525. DiPietro, L. A., Burdick, M., Low, Q. E., Kunkel, S. L., & Strieter, R. M. (1998). MIP-1 alpha as a critical macrophage chemoattractant in murine wound repair. Journal of Clinical Investigation, 101, 1693–1698. Guan, E., Wang, J., Rodriguez, G., & Norcross, M. A. (2002). Natural truncation of the chemokine MIP-1 beta/CCL4 affects receptor specificity but not anti-HIV-1 activity. Journal of Biological Chemistry, 277, 32348–32352. Homey, B., Muller, A., & Zlotnik, A. (2002). Chemokines: Agents for the immunotherapy of cancer? Natural Review on Immunology, 2, 175–184. Horuk, R. (2003). Development and evaluation of pharmaceutical agents targeting chemokine receptors. Methods, 29, 369–375. Lee, J. K., Lee, E. H., Yun, Y. P., Kim, K., Kwack, K., Na, D. S., Kwon, B. S., & Lee, C.-K. (2002). Truncation of the NH2-terminal amino acid residues increases agonistic potency of leukotactin-1 on CC chemokine receptors 1 and 3. Journal of Biological Chemistry, 277, 14757–14763. Luther, S. A., & Cyster, J. C. (2001). Chemokines as regulators of T cell differentiation. Nature, 2, 102–107. Menten, P., Wuyts, A., & von Damme, J. (2002). Macrophage inflammatory protein-1. Cytokine Growth Factor Reviews, 13, 455–481.
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M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Murdoch, C., & Finn, A. (2000). Chemokine receptors and their role in inflammation and infectious diseases. Blood, 95, 3032– 3043. Proost, P., Menten, P., Struyf, S., Schutyser, E., De Meester, I., & Van Damme, J. (2000). Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist. Blood, 96, 1674– 1680. Proudfoot, A. E. I., Power, C. A., Rommel, C., & Wells, T. N. C. (2003). Strategies for chemokine antagonists as therapeutics. Seminars on Immunology, 15, 57–65. Venge, J., Lampinen, M., Hakansson, L., Rak, S., & Venge, P. (1996). Identification of IL-5 and RANTES as the major
eosinophil chemoattractants in the asthmatic lung. Journal of Allergy and Clinical Immunology, 97, 1110–1115. von Stebut, E., Metz, M., Milon, G., Knop, J., & Maurer, M. (2003). Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1␣/ released from neutrophils recruited by mast cell-derived TNF␣. Blood, 101, 210–215. Wolf, M., Clark-Lewis, I., Buri, C., Langen, H., Lis, M., & Mazzucchelli, L. (2003). Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. American Journal of Pathology, 162, 1183–1190.
Molecules in focus
Macrophage inflammatory protein-1 M. Maurer∗ , E. von Stebut Department of Dermatology, University of Mainz, Langenbeckstr. 1, Mainz 55101, Germany Received 5 September 2003; received in revised form 27 October 2003; accepted 27 October 2003
Abstract Macrophage inflammatory protein (MIP)-1␣ was identified 15 years ago as the first of now four members of the MIP-1 CC chemokine subfamily. These proteins termed CCL3 (MIP-1␣), CCL4 (MIP-1), CCL9/10 (MIP-1␦), and CCL15 (MIP-1␥) 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 (M), 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. © 2003 Elsevier Ltd. All rights reserved. Keywords: Chemokine; MIP-1; CCL3; CCL4; CCR5
1. Introduction
2. Structure
Two recent and important findings have led to a renewed interest in MIP-1 proteins (MIP-1␣, , ␥, ␦), highly related ligands and activators of CC chemokine receptors (mainly CCR1, 3, and 5): (1) the M effector chemokines CCL3 and CCL4, which are produced and secreted by activated M to attract other proinflammatory cells, are also crucial in recruiting M themselves to sites of inflammation; and (2) CCL3 can potently inhibit the M uptake of HIV-1 via CCR5 ligation.
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-1␣, human: MIP-1␣/LD78␣) and CCL4 (mice and human: MIP-1) 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 murine and human CCL3 and CCL4 proteins are synthesized as 92 aa precursors. Mature secreted proteins (69–70 aa) are generated by peptidases that cleave hydrophobic signal peptides, most of which have recently been identified (Menten, Wuyts, & von Damme, 2002). Other MIP-1 proteins such as CCL3L1/MIP-1␣/LD78, CCL15/MIP-1␦ in humans or CCL9/10/MIP-1␥ in mice are not as well
∗ Corresponding author. Tel.: +49-6131-17-5293; fax: +49-6131-17-6614. E-mail address: [email protected] (M. Maurer).
1357-2725/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2003.10.019
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
1883
Fig. 1. Gene and protein structures of MIP-1. (A) Comparison of human and murine MIP-1␣/ genes. Horizontal lines represent intron sequences, boxes represent exon sequences: gray = untranslated leader sequences, green = translated leader sequences, red = translated mature protein sequences. Numbers indicate the lengths of segments. (B) Comparison of primary structures of mature MIP-1 proteins.
characterized in terms of gene and protein structure (Table 1). At physiologically relevant concentrations, i.e. <100 ng/ml, CCL3 is found only in its monomeric form, whereas dynamic and reversible aggregation occurs at higher concentrations. While self-aggregation does not influence MIP-1 bioactivity, binding to proteoglycans such as heparin appears to enhance it (Menten et al., 2002).
3. 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. M, Tand 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 activation, although low level baseline expression can sometimes be detected in unstimulated cells, e.g. in neutrophils. MIP-1 production can be induced by various proinflammatory agents/cytokines including LPS, substance P, viral infection, TNF␣, IFN␥, IL-1␣/ and others, whereas
treatment with IL-4, IL-10, dexamethason or other anti-inflammatory signals is known to downregulate MIP-1 expression. There is only limited information on the degradation and biological half life of MIP-1. Recent studies suggest that MIP-1 activity may be limited by proteases, e.g. cathepsin D, as both CCL3 and CCL4 are cleaved and inactivated by this enzyme (Wolf et al., 2003). On the other hand, proteolytic truncation of MIP-1 proteins, i.e. CCL3L1 (MIP-1␣/LD78), CCL4, and CCL15, can also increase their bioactivity (Proost et al., 2000; Lee et al., 2002; Guan, Wang, Rodriguez, & Norcross, 2002).
4. 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 complex leading to its
a
Mo: monocytes, N: neutrophils, Eo: eosinophils, T: T-cells, Baso: basophils, DC: dendritic cells, ?: not known.
CCL3, RANTES, MCP-2, HCC-1, M-tropic HIV-1 CCL3, RANTES, MCP-2, HCC-1, M-tropic HIV-1 CCL15, RANTES, MPIF-1, MCP-2,3, HCC-1/4 CCL15, RANTES, MPIF-1, MCP-2,3, HCC-1/4 RANTES, MCP-2/3, Eotaxin(-2/3), MEC (Mo > T, DC) (Mo > T, DC) (Mo > N > Eo) (Mo = N > Eo) (Eo > Baso, T) CCR5 CCR5 CCR1 CCR1 CCR3 MIP-1 11 (654 bp) MIP-1␥ 11 (1255 bp) ? ? 17 (960 bp) 17 (696 bp) ? 17 (955–1392 bp) MIP-1 ? MIP-1␦/Lkn-1 CCL4 CCL9/10 CCL15
MIP-1␣ 11 (764 bp) MIP-1␣/LD78␣ (MIP-1␣/LD78) CCL3 (CCL3L1)
Ligand Chromosome (transcript size in base pairs (bp)) Ligand
Chromosome (transcript size in base pairs (bp))
Receptor (expression by) Mouse Human
MIP-1 chemokine subfamily
Table 1 MIP-1 proteins and their receptorsa
17 (776 bp)
CCR1 (Mo, T > N > Eo) CCL15, RANTES, MPIF-1, MCP-2,3, HCC-1/4
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Selected alternative ligands
1884
dissociation into G␣ and G␥ subunits (Proudfoot, Power, Rommel, & Wells, 2003). G␣ induces phosphoinositide 3-kinase (PI3K) pathway activation, and G␥ subunits activate phospholipase C and induce Ca2+ influx resulting in protein kinase C isoform activation. It has also been shown that MAP kinases as well as the JAK/STAT signaling cascade are involved. The exact downstream events induced by CCL3 and CCL4 remain to be characterized. MIP-1 receptors, as all CCRs, bind several different chemokines, whereas MIP-1 proteins exhibit (relatively) high receptor specificity (Table 1). MIP-1 family members orchestrate acute and chronic inflammatory host responses at sites of injury or infection mainly by recruiting proinflammatory cells (compare Table 1). They are crucial for T-cell chemotaxis from the circulation to inflamed tissue and also play an important role in the regulation of transendothelial migration of monocytes, dendritic cells, and NK cells. Neutrophils and eosinophils are less responsive to the chemotactic effects of MIP-1: CCL3 can only recruit IFN␥-activated neutrophils and only small subpopulations of CCR1 expressing eosinophils. CCR1, CCR3, and CCR5 activation by MIP-1 also leads to Ca2+ release, upregulation of activation markers and release of proinflammatory mediators such as LTC4 , arachidonic acid or histamine. In addition, MIP-1 proteins can regulate immune responses by modulating Th-differentiation. CCL3 and its receptor CCR5 promote Th1 skewing, e.g. CCR5-deficient mice display Th2-skewed cytokine profiles (Andres et al., 2000), whereas Th2 cells mainly express CCR2 and CCR4 (Luther & Cyster, 2001). Thus, it is not surprising that MIP-1 proteins are key players in the pathogenesis of many inflammatory conditions and diseases (Fig. 2) including asthma, granuloma formation, wound healing, arthritis, multiple sclerosis (murine EAE model), pneumonia, and psoriasis (Murdoch & Finn, 2000). For example, CCL3 and CCL4 released from neutrophils that are recruited to sites of skin injury by mast cell-derived TNF␣ were found to be crucial mediators for M influx in a murine model of cutaneous granuloma formation (von Stebut, Metz, Milon, Knop, & Maurer, 2003). CCL3 also appears to be the critical M chemoattractant in cutaneous wound repair, where it promotes healing (DiPietro et al., 1998), and it
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Fig. 2. Selection of human diseases promoted by MIP-1 proteins.
contributes to antigen-dependent basophil chemotaxis, histamine release and the development of eosinophilia in a model of allergic asthma (Venge, Lampinen, Hakansson, Rak, & Venge, 1996). MIP-1 proteins can also promote health by inducing inflammatory responses against infectious pathogens such as viruses, e.g. influenza (Menten et al., 2002) or parasites (Aliberti et al., 2000). For example, in Toxoplasma gondii infection CCL3 and CCL4 (and CCL5/RANTES) increase IL-12 release from dendritic cells by binding to CCR5, which results in enhanced Th1 immunity and clearance of the parasite (Venge et al., 1996). On the other hand, the MIP-1 receptors CCR3 and CCR5 promote HIV-1 infection as they are important co-receptors for M-tropic HIV-1 viruses on CD4+ target cells (Horuk, 2003). In summary, MIP-1 plays a key role in the induction and modulation of inflammatory responses, i.e. in the context of autoimmune reactions and host defense responses (Fig. 2). In addition, MIP-1 proteins also regulate various aspects of tissue homeostasis. In the interest of space, these important physiological MIP-1 functions, e.g. in thymic and stem cell development, angiogenesis, and tumor biology, which are discussed in excellent recent reviews (Menten et al., 2002; Homey, Muller, & Zlotnik, 2002), are not considered here.
5. Possible medical applications During the past years rapid advances have been made in the identification and characterization of
1885
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 autoimmune and other inflammatory diseases (e.g. multiple sclerosis, organ transplant rejection, rheumatoid arthritis, asthma); (2) to identify specific and potent virus uptake inhibitors that block HIV-1 entry via its major co-receptor CCR5 (Horuk, 2003). References Aliberti, J., Reis e Sousa, C., Schito, M., Hieny, S., Wells, T., Huffnagle, G. B., & Sher, A. (2000). CCR5 provides a signal for microbial induced production of IL-12 by CD8 alpha+ dendritic cells. Natural Immunology, 1, 83–87. Andres, P. G., Beck, P. L., Mizoguchi, E., Mizoguchi, A., Bhan, A. K., Dawson, T., Kuziel, W. A., Maeda, N., MacDermott, R. P., Podolsky, D. K., & Reinecker, H. C. (2000). Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: Lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. Journal on Immunology, 164, 6303–6312. Carter, P. H. (2002). Chemokine receptor antagonism as an approach to anti-inflammatory therapy: Just right or plain wrong? Current Opinion in Chemical Biology, 6, 510–525. DiPietro, L. A., Burdick, M., Low, Q. E., Kunkel, S. L., & Strieter, R. M. (1998). MIP-1 alpha as a critical macrophage chemoattractant in murine wound repair. Journal of Clinical Investigation, 101, 1693–1698. Guan, E., Wang, J., Rodriguez, G., & Norcross, M. A. (2002). Natural truncation of the chemokine MIP-1 beta/CCL4 affects receptor specificity but not anti-HIV-1 activity. Journal of Biological Chemistry, 277, 32348–32352. Homey, B., Muller, A., & Zlotnik, A. (2002). Chemokines: Agents for the immunotherapy of cancer? Natural Review on Immunology, 2, 175–184. Horuk, R. (2003). Development and evaluation of pharmaceutical agents targeting chemokine receptors. Methods, 29, 369–375. Lee, J. K., Lee, E. H., Yun, Y. P., Kim, K., Kwack, K., Na, D. S., Kwon, B. S., & Lee, C.-K. (2002). Truncation of the NH2-terminal amino acid residues increases agonistic potency of leukotactin-1 on CC chemokine receptors 1 and 3. Journal of Biological Chemistry, 277, 14757–14763. Luther, S. A., & Cyster, J. C. (2001). Chemokines as regulators of T cell differentiation. Nature, 2, 102–107. Menten, P., Wuyts, A., & von Damme, J. (2002). Macrophage inflammatory protein-1. Cytokine Growth Factor Reviews, 13, 455–481.
1886
M. Maurer, E. von Stebut / The International Journal of Biochemistry & Cell Biology 36 (2004) 1882–1886
Murdoch, C., & Finn, A. (2000). Chemokine receptors and their role in inflammation and infectious diseases. Blood, 95, 3032– 3043. Proost, P., Menten, P., Struyf, S., Schutyser, E., De Meester, I., & Van Damme, J. (2000). Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist. Blood, 96, 1674– 1680. Proudfoot, A. E. I., Power, C. A., Rommel, C., & Wells, T. N. C. (2003). Strategies for chemokine antagonists as therapeutics. Seminars on Immunology, 15, 57–65. Venge, J., Lampinen, M., Hakansson, L., Rak, S., & Venge, P. (1996). Identification of IL-5 and RANTES as the major
eosinophil chemoattractants in the asthmatic lung. Journal of Allergy and Clinical Immunology, 97, 1110–1115. von Stebut, E., Metz, M., Milon, G., Knop, J., & Maurer, M. (2003). Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1␣/ released from neutrophils recruited by mast cell-derived TNF␣. Blood, 101, 210–215. Wolf, M., Clark-Lewis, I., Buri, C., Langen, H., Lis, M., & Mazzucchelli, L. (2003). Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. American Journal of Pathology, 162, 1183–1190.