Inhibition of soluble immune response suppressor activity by growth factors

Soluble immune response suppressor (SIRS), a protein of Mr 14,000, is a lymphokine produced by interferon- or concanavalin A-activated suppressor T cells and is oxidized to its activated form, SIRSox, by H2O2 produced by macrophages. SIRSox inhibits antibody secretion by B lymphocytes and cell division by normal or transformed cell lines. Effects of purified growth factors on suppression of antibody secretion were examined to determine whether any would oppose the inhibitory effects of SIRS or SIRSox. Interleukin 1 (IL-1), interleukin 2 (IL-2), and epidermal growth factor (EGF) each inhibited SIRS-mediated suppression of antibody secretion by cultured mouse spleen cells. Inhibition of SIRS activity was most effective when growth factors were added late in the culture period. IL-1, IL-2, and EGF also blocked suppression by SIRSox. However, EGF and IL-1 blocked suppression by SIRSox only when added 3-6 hr before addition of SIRSox, whereas IL-2 blocked suppression by SIRSox when added before or up to 3 hr after addition of SIRSox. Further evaluation showed that IL-2, but not EGF or IL-1, reversed inhibition of antibody secretion by SIRSox in a time- and concentration-dependent manner. With 50 units of IL-2 per 0.5-ml culture, reversal was complete within 1 hr. The ability of growth factors to interfere with inhibition of cell division by SIRSox was examined with the human B-cell leukemia RPMI-1788. This cell line binds EGF but is not known to have cell surface receptors for IL-1 or IL-2. EGF (0.3-1 ng/ml), when added to RPMI-1788 cultures 4-6 hr before SIRSox, interfered with the ability of SIRSox to inhibit cell division. Taken together, these data indicate that growth factors interfere with both the immunosuppressive and growth inhibitory properties of SIRSox in both heterogeneous and homogeneous cell populations.