IL-4 EXPRESSION IN HUMAN T-CELLS IS SELECTIVELY INHIBITED BY IL-1-ALPHA AND IL-1-BETA

Imbalances in anti-inflammatory and proinflammatory cytokines may be r esponsible for initiation or progression of diverse pathologic states including autoimmune and infectious diseases. IL-4 inhibits production of proinflammatory cytokines and IL-12 promotes differentiation and a ctivation of IFN-gamma-producing T cells, but does a counter-regulator y effect of proinflammatory cytokines on IL-4 production exist? This s tudy evaluates the effect of proinflammatory cytokines (IL-1 alpha, IL -1 beta, IL-6, IL-12, and TNF-alpha) on IL-4 production in primary hum an T cell cultures. PBMCs from healthy individuals were tested for IL- 4 production in response to PHA and various cytokines. IL-4 was measur ed by proliferation of the IL-4-sensitive T cell line (CT.h4S) or ELIS A. IL-1 alpha and IL-1 beta inhibited IL-4 production by 20 to 80% in >92% of healthy individuals (p = 0.0001, paired t-test). IL-12 had an inhibitory effect on PBMC IL-4 production as previously described, but neither IL-6 nor TNF-alpha inhibited IL-4 production. IL-1 had no eff ect on PHA-induced PBMC or purified T cell proliferation or IL-2 produ ction. IL-4 production by purified T cells stimulated by PHA or the co mbination of PMA with calcium ionophore (A23187) was inhibited by IL-1 , and reconstitution with peripheral blood-derived adherent macrophage s had no effect. IL-12 did not inhibit IL-4 production in stimulated p urified T cells, Steady state IL-4 mRNA levels were determined by semi quantitative competitive reverse transcribed PCR (RT-PCR). Marked inhi bition of IL-4 mRNA levels were seen at 5 h after exposure to IL-1. Th is interaction between IL-1 and IL-4 may be an important physiologic r egulator of the balance between proinflammatory cytokines from activat ed macrophages and anti-inflammatory cytokines from T cells.