title: Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP/PKA signaling pathway.
abstract: One of the major characteristics of tumors is their ability to evade immunosurveillance through altering the properties and functions of host stromal and/or immune cells. CCL5 has been shown to play important roles in T cell proliferation, IFN-γ, and IL-2 production, which promotes the differentiation and proliferation of Th1 cells important for immune defense against intracellular infection. In this study we found that tumor-bearing mice were more susceptible to bacterial infection and showed reduced CCL5 levels in serum during endotoxic shock. Our data further demonstrated that the soluble factors secreted by mammary gland tumor cells but not normal mammary gland epithelial cells inhibited CCL5 expression in macrophages in response to LPS, but not to TNF-α stimulation. The inhibitory effect of tumor-secreted molecules on LPS-induced CCL5 expression was regulated at the post-transcriptional level. Blocking PGE(2) synthesis by NS398 or through the use of PGE(2) receptor antagonists AH-6809 (EP2 antagonist) and AH-23848 (EP4 antagonist) completely reversed the inhibitory effect of tumor-conditioned medium (TCM) on LPS-induced CCL5 expression. Moreover, PGE(2) and the cAMP analog forskolin could mimic tumor-mediated CCL5 inhibition, and the inhibitory effects of TCM, PGE(2), and cAMP analog on LPS-induced CCL5 expression could be completely reversed by the PKA inhibitor H89. Furthermore, blocking PGE(2) synthesis in vivo led to partial recovery of CCL5 production during endotoxic shock. Taken together, our data indicate that PGE(2) secreted from breast cancer cells suppresses CCL5 secretion in LPS-activated macrophages through a cAMP/PKA signaling pathway, which may result in suppression of host immune responses against subsequent bacterial infection.
authors.affiliation: Division of Immunobiology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Qian
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001424:Bacterial Infections / Q000378:metabolism; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D019139:Tumor Escape / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D007376:Interleukin-2; D007546:Isoquinolines; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D011448:Prostaglandin Antagonists; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D044004:Xanthones; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005576:Colforsin; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D007371:Interferon-gamma; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide