GRANULOCYTE-COLONY-STIMULATING FACTOR DOWN-REGULATES ALLOGENEIC IMMUNE-RESPONSES BY POSTTRANSCRIPTIONAL INHIBITION OF TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

We report downregulatory effects of granulocyte colony-stimulating fac tor (G-CSF) on allogeneic immune responses in vitro. G-CSF did not aff ect the proliferative response of peripheral blood mononuclear cells ( PBMC) against allogeneic Daudi cells but did inhibit tumor necrosis fa ctor (TNF)-alpha secretion. In contrast with G-CSF, granulocyte-macrop hage (GM)-CSF and interleukin (IL)-3 enhanced alloactivation-induced T NF-alpha production. G-CSF-mediated suppression of TNF-alpha productio n was not affected by fixation of stimulators. G-CSF did not inhibit T NF-alpha mRNA expression or accelerate mRNA degradation, whereas pento xifylline inhibited the expression of TNF-alpha mRNA. These results in dicate that G-CSF acts directly on responder cells and modulates TNF-a lpha production at posttranscriptional levels. Suppression of TNF-alph a secretion was accompanied by an increase of intracellular cyclic ade nosine monophosphate (cAMP) concentration in alloactivated PBMC. The c ell permeable cAMP analogue, dibutyryl cAMP, suppressed TNF-alpha secr etion without affecting TNF-alpha mRNA expression, G-CSF showed an inh ibitory effect on the development of cytotoxic effector cells against allogeneic Daudi cells. Anti-TNF-alpha monoclonal antibody (MoAb) also inhibited the induction of cytolytic activity, and the inhibitory eff ects of G-CSF and anti-TNF-alpha MoAb on killer activity generation we re overcome by adding exogenous TNF-alpha. Hence, impaired generation of cytolytic effector cells by G-CSF is believed to be the result of r educed TNF-alpha production, Collectively, the results described above suggest that G-CSF downregulates allogeneic immune responses by postt ranscriptionally inhibiting TNF-alpha production. (C) 1995 by The Amer ican Society of Hematology.