Suppression of lymphokine-activated killer (LAK) cell induction mediated by interleukin-4 and transforming growth factor-β1: effect of addition of exogenous tumour necrosis factor-alpha and interferon-gamma, and measurement of their endogenous production

Abstract

Summary Recombinant human interleukin-4 (rhlL-4) and transforming growth factor-βl (TGF-β1) suppressed the induction of lymphokine-activated killer (LAK) activity induced by recombinant human interleukin-2 (rhIL-2) in peripheral blood lymphocytes. DNA synthesis and the expression of the p55 alpha chain of the IL-2 receptor (Tac antigen) were also inhibited. The inhibitory effect was greatest when these factors were added during the first 48 h of a 4-day culture, with reduced cytolytic activity against both natural killer (NK) resistant and NK-sensitive tumour cell line targets. The suppressive action of both cytokines was accompanied by a reduction in tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) levels in lymphocyte culture supernatants. Recombinant human IFN-γ (rhIFN-γ). but not recombinant human TNF-α (rhTNF-α) was able to overcome the inhibitory effect of recombinant human interleukin-4(rhIL-4) on LAK induction and DNA synthesis but not Tac antigen expression. However, cytotoxicity induced by rhI FN-γ alone was also suppressed by rhIL-4 and TGF-β1, inferring that rhIFN-γ-mediated abrogation of rhlL-4 suppression was not simply a direct IL-2-indcpendent effect on cytotoxicity. In addition, rhIL-4 did not increase TGF-β production from rhIL-2-activated peripheral blood mononuclear cells, suggesting that rhIL-4 did not mediate reduction of rhIL-2 responses through the induction of TGF-β release.