Murine Th1 and Th2 cell clones differentially regulate macrophage nitric oxide production.
Previous studies have demonstrated that the combination of the T helper cell 1 (Th1)-derived cytokines interleukin (IL)-2 and interferon (IFN)-gamma induces nitric oxide (NO) production and tumor cytolysis by mouse peritoneal macrophages and the mouse macrophage cell line ANA-1 in vitro. Conversely, the Th2-derived cytokine IL-4 inhibits IL-2 and IFN-gamma-induced NO production and tumor cytolysis by ANA-1 macrophages. To examine the paracrine regulatory effects of Th1 and Th2 cells on macrophages, various mouse T cell clones were tested for their ability to regulate NO production by mouse peritoneal macrophages or ANA-1 macrophages. Antigen, superantigen, and mitogen stimulated Th1 cells but not Th2 cells induced NO production by macrophages. Supernatants from these activated Th1 clones also induced NO production by peritoneal macrophages and ANA-1 macrophages. Neutralization analysis using monoclonal anticytokine antibodies revealed that both IL-2 and IFN-gamma production by activated Th1 cells were required for the production of NO by macrophages. Co-culture studies using a panel of Th2 cell clones that share the same antigen specificity revealed that these cells suppressed Th1-mediated macrophage activation. The Th2-mediated impairment of Th1-induced NO production was primarily due to the secretion of IL-4. IL-4 appeared to have a direct effect on macrophage activation because neither mitogen-induced proliferation of Th1 cells nor cytokine production by Th1 cells were affected by IL-4. Overall, these results suggest that a potent paracrine regulatory network involving Th1 cells and Th2 cells may control the activation of macrophages for NO production and antitumor cytotoxicity.
Taub
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DD
Clinical Services Program, Program Resources, Inc., DynCorp, Frederick, Maryland 21702, USA.
Cox
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GW
D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis*; D018089:Superantigens / Q000276:immunology; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009569:Nitric Oxide