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 μM). 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 μM. 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 μM). 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 μM 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 anti-oxidants in mycobacterial infections.