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.
Stout
R D
RD
Department of Microbiology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614.
Suttles
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D000818:Animals; D000906:Antibodies; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D000906:Antibodies; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D007371:Interferon-gamma