Endogenous interferon alpha/beta produced by Kupffer cells inhibits interleukin-1, tumor necrosis factor alpha production and interleukin-2-induced activation of nonparenchymal liver cells.

We have previously reported liver-specific interferon (IFN) alpha/beta production by murine Kupffer cells that was not observed with other tissue macrophages incubated in the absence of stimulators such as IFN gamma or lipopolysaccharide (LPS). Consequently, while interleukin-2 (IL-2) alone induced pronounced lymphokine-activated killer (LAK) activity from splenocytes, combination of anti-IFN alpha/beta antibody with IL-2 was required to generate significant LAK activity from nonparenchymal liver cells. This endogenous IFN alpha/beta production by Kupffer cells was not induced by LPS because (a) addition of polymyxin B did not abolish the positive effects of anti-IFN alpha/beta antibody on nonparenchymal liver cells, and (b) similar results were obtained when comparing the responses of LPS-responsive C3HeB/FeJ and LPS-hyporesponsive C3H/HeJ mice. The possibility of hepatotropic infection was also ruled out in that anti-IFN alpha/beta antibody enhanced hepatic but not splenic LAK cell induction in vitro in both conventional and germ-free C3H/HeN mice. IFN alpha/beta played an autoregulatory role by down-regulating the production of IL-1 and tumor necrosis factor alpha by Kupffer cells. However, the augmenting effect of anti-IFN alpha/beta antibody on LAK induction from non-parenchymal liver cells was not mediated through an increase in the level of either IL-1 or TNF alpha, as specific antisera against either cytokine did not abrogate this positive effect. Finally, flow-cytometry analysis showed that IFN alpha/beta significantly diminished the expression of IL-2 receptor alpha chain, indicating an inhibition of LAK cell generation at a relatively early stage of induction.