Evidence for involvement of TNF-alpha in the induction phase and IFN-beta in the effector phase of antiproliferative activity of splenic macrophages.

Splenic macrophages play a key role in regulating cell proliferation during a variety of chronic perturbations of the hematopoietic system. This regulatory activity is in sharp contrast to the activities of inflammatory monocytes/macrophages in that it is not dominated by the secretion of prostaglandins or toxic metabolites such as peroxides. A productive model for studying these nontoxic regulatory activities of splenic macrophages has been provided by macrophages generated in vitro (M phi-c) during autologous spleen cell culture. The M phi-c effectively inhibit (greater than 90%) lymphocyte proliferation by inhibiting G1----S phase progression without inhibiting the production of interleukins by the lymphocytes. Conditioned medium from M phi-c activated with LPS + rIFN-gamma effected a similar G1 arrest of activated lymphocytes. The involvement of IFN-beta in effecting the antiproliferative activity is suggested by (1) the ability of monospecific anti-IFN-beta mAB, but not anti-TGF-beta, anti-IL-1, anti-TNF-alpha, or anti-IFN-gamma, to neutralize the antiproliferative activity in the M phi-c supernatants and (2) the ability of purified IFN-beta to effect a similar inhibition of cell proliferation (i.e., G1 arrest without inhibition of interleukin production). rTNF-alpha and rIFN-gamma could not effect such an inhibition of cell proliferation and did not synergize with IFN-beta in producing such an antiproliferative effect. The M phi-c could be activated to effector function by a combination of LPS + rIFN-gamma or rTNF-alpha + rIFN-gamma, but not by any one of those reagents alone. LPS alone was sufficient to stimulate TNF-alpha production by the M phi-c. Activation of the M phi-c by LPS + rIFN-gamma could be completely blocked by anti-TNF-alpha antibodies. These data suggest that the M phi-c can be induced to produce inhibitory levels of cytostatic cytokines by a TNF-alpha autocrine loop that is IFN-gamma dependent. The in vivo relevance of this effector mechanism is suggested by, and discussed in the context of, the recent reports of "spontaneous" production of IFN-beta during immunological disorders.