INTERLEUKIN-6 IS A MEDIATOR OF TNF-ALPHA REGULATION OF LAK CELL-FUNCTION

TNF-alpha at 50-100 U/ml synergizes with IL-2 in enhancing LAK activit y and IL-6 produCtion in low-dose IL-2 (1-10 U/ml) culture of human PB L. High-dose TNF-alpha (greater-than-or-equal-to 200 U/ml) has less ef fect and even sometimes resulted in lowering of both LAK activity and IL-6 production below control levels. TNF-alpha-mediated regulation of low-dose IL-2 activation occurs even at late stages (effector phase) of LAK development. IL-6, as previously reported, acts at late stages of low-dose 1L-2 culture to enhance LAK, but does not stimulate TNF-al pha production. The combined addition of TNF-alpha and IL-6 to late st ages of IL-2 culture does not produce any additive or synergistic effe ct on LAK. We tested for the relative roles of TNF-alpha and IL-6 in l ate stage regulation of LAK development with antibodies (Abs) to these cytokines. Anti-IL-6 Ab abrogates late phase LAK enhancement by TNF-a lpha, while anti-TNF-alpha Ab has no effect on IL-6 augmentation of LA K cytotoxicity. IL-2 added to PBL culture at doses greater than 10 U/m l induces production of both TNF-alpha and IL-6. Addition of anti-TNF- alpha Ab at late stages of high-dose IL-2 (greater-than-or-equal-to 20 U/ml) culture decreases both LAK cytotoxicity and IL-6 production, an d the inhibition of LAK is reversed by the addition of IL-6. By contra st, anti-IL-6 Ab decreases LAK cytotoxicity, but does not alter TNF-al pha production, and the inhibition of LAK is not reversed by addition of TNF-alpha. These data indicate that TNF-alpha is important for both LAK development and IL-6 secretion in PBL, and that IL-6 is the proxi mate mediator in TNF-alpha regulation of these cytotoxic cell function s.