Title

Evidence for Involvement of TNF-α in the Induction Phase and IFN-β in the Effector Phase of Antiproliferative Activity of Splenic Macrophages

Document Type

Article

Publication Date

1-1-1992

Description

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 (Mø-c) during autologous spleen cell culture. The Mø-c effectively inhibit (>90%) lymphocyte proliferation by inhibiting G1→S phase progression without inhibiting the production of interleukins by the lymphocytes. Conditioned medium from Mø-c activated with LPS + rIFN-γ effected a similar G1 arrest of activated lymphocytes. The involvement of IFN-β in effecting the antiproliferative activity is suggested by (1) the ability of monospecific anti-IFN-β mAB, but not anti-TGF-β, anti-IL-1, anti-TNF-α, or anti-IFN-γ, to neutralize the antiproliferative activity in the Mø-c supernatants and (2) the ability of purified IFN-β to effect a similar inhibition of cell proliferation (i.e., G1 arrest without inhibition of interleukin production). rTNF-α and rIFN-γ could not effect such an inhibition of cell proliferation and did not synergize with IFN-β in producing such an antiproliferative effect. The Mø-c could be activated to effector function by a combination of LPS + rIFN-γ or rTNF-α + rIFN-γ, but not by any one of those reagents alone. LPS alone was sufficient to stimulate TNF-α production by the Mø-c. Activation of the Mø)-c by LPS + rIFN-γ could be completely blocked by anti-TNF-a antibodies. These data suggest that the Mø-c can be induced to produce inhibitory levels of cytostatic cytokines by a TNF-α autocrine loop that is IFN-γ 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-β during immunological disorders.

Link to Full Text
COinS