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.
Tzung
S P
SP
Division of Gastroenterology and Hepatology, VA Medical Center, Buffalo, NY 14215.
Cohen
S A
SA
D000818:Animals; D005260:Female; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D016899:Interferon-beta / Q000494:pharmacology / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000502:physiology; D007728:Kupffer Cells / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000502:physiology; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology
D016898:Interferon-alpha; D007375:Interleukin-1; D007376:Interleukin-2; D008070:Lipopolysaccharides; D046911:Macromolecular Substances; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta