Prolactin regulates antitumor immune response through induction of tumoricidal macrophages and release of IL-12.
The involvement of PRL in regulating monocyte/macrophage functions is suggested by the presence of PRL-Rs in these cells. Here, we show that PRL, though it failed to activate mouse peritoneal resident macrophages (RMs), acted as a second signal and activated mouse peritoneal inflammatory macrophages (EMs) to a tumoricidal state. The cytotoxicity of mouse tumor-associated macrophages (TAMs) isolated at day 1 of tumor (Ehrlich ascites carcinoma, EAC) growth was enhanced by PRL. However, with progression of tumor growth, TAMs became nonresponsive to the hormone. PRL-induced killing of P815 target cells by EMs and TAMs was independent of TNF but correlated with the hormone-induced augmentation of NO2(-) and O2(-) release in these macrophages. Administration of PRL in vivo inhibited EAC growth and augmented NO2(-) release by TAMs. PRL synergized with the TH1 cytokine IFN-gamma, a known activator of macrophages, in inducing tumor killing and release of NO2(-) from EMs and TAMs. The hormone might activate macrophages at least partially, through the release of IFN-gamma as anti-IFN-gamma blocked IFN-gamma- as well as PRL-induced cytotoxicity in EMs. The TH2 cytokine IL-4 suppressed PRL-induced activation of macrophages. PRL induced release of IL-12 from EMs also, which suggested that the hormone might drive the TH1 response through IL-12. Our observations further suggest that PRL alone and in synergy with IFN-gamma, released through induction of IL-12, may generate tumoricidal macrophages and thus regulate the antitumor immune response of tumor hosts.
Majumder
Biswanath
B
Department of Immunoregulation and Immunodiagnosis, Chittaranjan National Cancer Institute, Kolkata, India.
Biswas
Ratna
R
Chattopadhyay
Utpala
U
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000502:physiology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010587:Phagocytosis; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism
D000276:Adjuvants, Immunologic; D017077:Culture Media, Conditioned; D009573:Nitrites; D011994:Recombinant Proteins; D013481:Superoxides; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D011388:Prolactin