iPLA2beta: front and center in human monocyte chemotaxis to MCP-1.
Monocyte chemoattractant protein-1 (MCP-1) directs migration of blood monocytes to inflamed tissues. Despite the central role of chemotaxis in immune responses, the regulation of chemotaxis by signal transduction pathways and their in vivo significance remain to be thoroughly deciphered. In this study, we examined the intracellular location and functions of two recently identified regulators of chemotaxis, Ca(2+)-independent phospholipase (iPLA(2)beta) and cytosolic phospholipase (cPLA(2)alpha), and substantiate their in vivo importance. These enzymes are cytoplasmic in unstimulated monocytes. Upon MCP-1 stimulation, iPLA(2)beta is recruited to the membrane-enriched pseudopod. In contrast, cPLA(2)alpha is recruited to the endoplasmic reticulum. Although iPLA(2)beta or cPLA(2)alpha antisense oligodeoxyribonucleotide (ODN)-treated monocytes display reduced speed, iPLA(2)beta also regulates directionality and actin polymerization. iPLA(2)beta or cPLA(2)alpha antisense ODN-treated adoptively transferred mouse monocytes display a profound defect in migration to the peritoneum in vivo. These converging observations reveal that iPLA(2)beta and cPLA(2)alpha regulate monocyte migration from different intracellular locations, with iPLA(2)beta acting as a critical regulator of the cellular compass, and identify them as potential targets for antiinflammatory strategies.
Mishra
Ravi S
RS
Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195, USA.
Carnevale
Kevin A
KA
Cathcart
Martha K
MK
D000199:Actins / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology*; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D005260:Female; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D054522:Group VI Phospholipases A2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009281:Naphthalenes / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D011753:Pyrones / Q000494:pharmacology
D000199:Actins; D001095:Arachidonic Acids; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D009281:Naphthalenes; D020319:Oligodeoxyribonucleotides, Antisense; D011753:Pyrones; C081565:arachidonyltrifluoromethane; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D054513:Group IV Phospholipases A2; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human