Receptors, signal transduction, and spectrum of action of monocyte chemotactic protein-1 and related chemokines

Sozzani, Silvano; Locati, Massimo; Zhou, Dan; Rieppi, Monica; Luini, Walter; Lamorte, Giuseppe; Bianchi, Giancario; Polentarutti, Nadia; Allavena, Paola; Mantovani, Alberto

doi:10.1002/jlb.57.5.788

Cited by 92 publications

(60 citation statements)

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“…The majority of studies have used pharmacologic inhibitors to understand possible pathways that may be involved. Some pathways that have been implicated as regulators of monocyte chemotaxis to MCP-1 include phosphatidylinositol 3 kinase, mitogen-activated protein kinases, protein kinase C, and PLA 2 (23,(41)(42)(43). Although studies from knockout mice indicate the importance of phosphatidylinositol 3 kinase in macrophage chemotaxis to a variety of stimuli, chemotaxis to MCP-1 was not evaluated (44).…”

Section: Discussionmentioning

confidence: 99%

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Calcium-Independent Phospholipase A2 Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1

Carnevale

Cathcart

2001

The Journal of Immunology

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Monocyte chemoattractant protein 1 (MCP-1) has an important influence on monocyte migration into sites of inflammation. Our understanding of the signal transduction pathways involved in the response of monocytes to MCP-1 is quite limited yet potentially significant for understanding and manipulating the inflammatory response. Prior studies have demonstrated a crucial regulatory role for cytosolic phospholipase A2 (cPLA2) in monocyte chemotaxis to MCP-1. In these studies we investigated the role for another PLA2, calcium-independent PLA2 (iPLA2) in comparison to cPLA2. Pharmacological inhibitors of PLA2 were found to substantially inhibit chemotaxis. Using antisense oligodeoxyribonucleotide treatment we found that iPLA2 expression is required for monocyte migration to MCP-1. Complete blocking of the chemotactic response was observed with inhibition of either iPLA2 or cPLA2 expression by their respective antisense oligodeoxyribonucleotide. In reconstitution experiments, lysophosphatidic acid completely restored MCP-1-stimulated migration in iPLA2-deficient monocytes, whereas lysophosphatidic acid was without effect in restoring migration in cPLA2-deficient monocytes. To the contrary, arachidonic acid fully restored migration of cPLA2-deficient monocytes while having no effect on the iPLA2-deficient monocytes. Additional studies revealed that neither enzyme appears to be upstream of the other indicating that iPLA2 and cPLA2 represent parallel regulatory pathways. These data demonstrate novel and distinct roles for these two phospholipases in this critical step in inflammation.

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Section: Discussionmentioning

confidence: 99%

“…CCR2 is one of numerous serpentine receptors characterized by seven-transmembrane domains and coupled to a GTP binding protein (23). When MCP-1 binds to CCR2 it induces a rapid (15 s) and transient (15 min) release of [ 3 H]arachidonic acid (AA) from radiolabeled human monocytes (24,25).…”

mentioning

confidence: 99%

Calcium-Independent Phospholipase A2 Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1

Carnevale

Cathcart

2001

The Journal of Immunology

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“…Even though we cannot rule out the possibility that Ca 2ϩ influx, too low to detect by the methods we used, is involved in chemotaxis, we consider it unlikely. Whether the Ca 2ϩ influx associated with chemokine binding to cell surface receptors is necessary for chemotaxis has been uncertain (39). Cell migration has been previously observed in the absence of calcium influx, and calcium influx has been observed without chemotaxis (40).…”

Section: Discussionmentioning

confidence: 99%

Monocyte Chemotactic Protein-1 Receptor CCR2B Is a Glycoprotein That Has Tyrosine Sulfation in a Conserved Extracellular N-Terminal Region

Preobrazhensky

Dragan

Kawano

et al. 2000

The Journal of Immunology

108

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Monocyte chemotactic protein-1 (MCP-1) binding to its receptor, CCR2B, plays an important role in a variety of diseases involving infection, inflammation, and/or injury. In our effort to understand the molecular basis of this interaction and its biological consequences, we recognized a conserved hexad of amino acids at the N-terminal extracellular domain of several chemokine receptors, including CCR2B. Human embryonic kidney 293 cells expressing Flag-tagged CCR2B containing site-directed mutations in this region, 21–26, including a consensus tyrosine sulfation site were used to determine MCP-1 binding and its biological consequences. The results showed that several of these amino acids are important for MCP-1 binding and consequent lamellipodium formation, chemotaxis, and signal transduction involving adenylate cyclase inhibition and Ca2+ influx into cytoplasm. Mutations that prevented adenylate cyclase inhibition and Ca2+ influx did not significantly inhibit lamellipodium formation and chemotaxis, suggesting that these signaling events are not involved in chemotaxis. CCR2B was found to be sulfated at Tyr26; this sulfation was abolished by the substitution of Tyr with Ala and severely reduced by substitution of Asp25, a part of the consensus sulfation site. The expressed CCR2B was found to be N-glycosylated, as N-glycosidase F treatment of the receptor or growth of the cells in tunicamycin reduced the receptor size to the same level, from 50 to 45 kDa. Thus, CCR2B is the first member of the CC chemokine receptor family shown to be a glycoprotein that is sulfated at the N-terminal Tyr. These post-translational modifications probably have significant biological functions.

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“…CCR 2 is one of 11 ␤-chemokine receptors characterized by seven transmembrane domains and coupled to a GTP-binding protein (18). When MCP-1 binds to CCR 2 , it results in increased arachidonic acid release and influx of extracellular calcium, which is inhibited by Bordetella pertussis toxin treatments (19 -21).…”

mentioning

confidence: 99%

“…When MCP-1 binds to CCR 2 , it results in increased arachidonic acid release and influx of extracellular calcium, which is inhibited by Bordetella pertussis toxin treatments (19 -21). Serine/threonine kinases are thought to be involved in post-CCR 2 signaling as a result of numerous studies using pharmacological inhibitors (18,(22)(23)(24). General serine/threonine inhibitors such as C1, staurosporine, and H7 have all been shown to inhibit MCP-1-induced chemotaxis in treated monocytes (22).…”

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confidence: 99%

Protein Kinase C β Is Required for Human Monocyte Chemotaxis to MCP-1

Carnevale

Cathcart

2003

Journal of Biological Chemistry

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Monocyte chemoattractant protein 1 (MCP-1) is important in attracting monocytes to sites of inflammation. Using predominantly pharmacological approaches, prior studies have indicated that serine/ threonine kinases are involved in the MCP-1-induced signaling pathways. We report here that there is substantial inhibition of MCP-1-stimulated chemotaxis of human monocytes treated with inhibitors selective for the subset of serine/threonine kinases, protein kinase C (PKC). Selective inhibitors of PKC such as GF109203X and Calphostin C both caused ϳ80% inhibition of chemotaxis. Because these pharmacological inhibitors do not specifically inhibit individual PKC isoforms, we chose to use antisense oligodeoxyribonucleotides (ODN) to specifically reduce PKC isoform expression, first by inhibiting expression of the conventional PKC family, and next by using specific antisense ODN for PKC␣ and PKC␤. Conventional PKC-antisense ODN treatment completely and significantly inhibited monocyte chemotaxis to MCP-1, whereas sense-control ODN caused no significant inhibition. PKC␤-antisense ODN caused 89.2% inhibition of chemotaxis at its highest dose. In contrast, PKC␤-sense ODN and PKC␣-antisense and -sense ODN were without effect. Further studies evaluating the calcium response that is triggered upon MCP-1 interaction with its receptor, CCR 2 , indicate that this response is not altered by antisense or sense ODN treatment, thus supporting our hypothesis that PKC␤ is critical for post-receptor signal transduction downstream of the immediate calcium signal. These data contribute to our developing understanding of the signal transduction pathways involved in the chemotactic response of human monocytes to MCP-1 and uniquely identify the requirement for the PKC␤ isoform in this important process.

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Receptors, signal transduction, and spectrum of action of monocyte chemotactic protein-1 and related chemokines

Cited by 92 publications

References 0 publications

Calcium-Independent Phospholipase A2 Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1

Calcium-Independent Phospholipase A2 Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1

Monocyte Chemotactic Protein-1 Receptor CCR2B Is a Glycoprotein That Has Tyrosine Sulfation in a Conserved Extracellular N-Terminal Region

Protein Kinase C β Is Required for Human Monocyte Chemotaxis to MCP-1

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