Nordihydroguaiaretic acid blocks IL-2-independent lymphocyte proliferation and enhances responses to PPD.
The authors examined the mechanism by which the non-specific lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) inhibits human lymphocyte proliferative responses and compared its effects with those of cyclosporine (CsA). It was found that CsA-resistant proliferative responses induced by direct PK-C activators such as mitogenic concentrations of the phorbol ester TPA or the putative antitumour agent bryostatin 1 (bryo 1) were inhibited in a concentration-dependent manner by NDGA (IC50 = 2 microM). In contrast, CsA-sensitive IL-2-dependent proliferative responses induced by PHA, anti-CD3 or the purified protein derivative (PPD) of M. tuberculosis were not significantly inhibited by NDGA concentrations as high as 8 microM. The expression of the IL-2R by lymphocytes was also resistant to NDGA concentrations that effectively blocked the mitogenic effects of TPA or bryostatin, but could be inhibited by higher concentrations of NDGA (IC50 = 8 microM). In addition, NDGA, but not CsA, blocked the production of IL-6 by human mononuclear cells. Furthermore, PPD-induced proliferation was significantly enhanced by NDGA. These data would suggest that NDGA at concentrations below 8 microM selectively inhibits IL-2-independent proliferation. NDGA's ability to inhibit IL-6 while enhancing the proliferative response to PPD may indicate an anti-inflammatory therapeutic potential of antioxidants in mycobacterial infections.
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AH
Institut Pasteur, Departement d'Immunologie, Paris, France.
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PJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D054713:Bryostatins; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007783:Lactones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D018942:Macrolides; D009637:Masoprocol / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014373:Tuberculin / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D000276:Adjuvants, Immunologic; D054713:Bryostatins; D016572:Cyclosporine; D007376:Interleukin-2; D015850:Interleukin-6; D007783:Lactones; D016859:Lipoxygenase Inhibitors; D018942:Macrolides; D009637:Masoprocol; D013755:Tetradecanoylphorbol Acetate; D014373:Tuberculin; D000093242:Interleukin-6 Inhibitors; C046785:bryostatin 1