Regulation of cytosolic phospholipase A2 activity in macrophages stimulated with receptor-recognized forms of alpha 2-macroglobulin: role in mitogenesis and cell proliferation.
Macrophages exposed to receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) demonstrate increased DNA synthesis and cell division. In the current study, we have probed the role of cytosolic phospholipase A(2) (cPLA(2)) activity in the cellular response to alpha(2)M*. Ligation of the alpha(2)M* signaling receptor by alpha(2)M*, or its receptor binding fragment, increased cPLA(2) activity 2-3-fold in a concentration and time-dependent manner. This activation required a pertussis toxin-insensitive G protein. Cellular binding of alpha(2)M* also induced transient translocation of cPLA(2) activity to nuclei and membrane fractions. Inhibition of protein kinase C activity or chelation of Ca(2+) inhibited alpha(2)M*-induced increased cPLA(2) activity. Binding of alpha(2)M* to macrophages, moreover, increased phosphorylation of MEK 1/2, ERK 1/2, p38 MAPK, and JNK. Incubation of macrophages with inhibitors of MEK 1/2 or p38 MAPK before stimulation with alpha(2)M* profoundly decreased phosphorylation of MAPKs, blocking cPLA(2) activation. alpha(2)M*-induced increase in [(3)H]thymidine uptake and cell proliferation was completely abolished if activation of cPLA(2) was prevented. The response of macrophages to alpha(2)M* requires transcription factors nuclear factor kappaB, and cAMP-responsive element-binding protein as well as expression of the proto-oncogenes c-fos and c-myc. These studies indicate that the activation of cPLA(2) plays a crucial role in alpha(2)M*-induced mitogenesis and cell proliferation.
Misra
Uma Kant
UK
Department of Pathology, Duke University Medical Center, Durham, North Carolina 2771, USA.
Pizzo
Salvatore Vincent
SV
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D016762:Genes, fos; D016259:Genes, myc; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D054467:Phospholipases A2; D010766:Phosphorylation; D000511:alpha-Macroglobulins / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016328:NF-kappa B; D000511:alpha-Macroglobulins; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2