Suppression of hepatic lymphokine-activated killer cell induction by murine kupffer cells and hepatocytes

Tzung, Shie-Pon; Gaines, Katherine C.; Lance, Peter; Ehrke, M. Jane; Cohen, Steven D.

doi:10.1002/hep.1840120404

Cited by 15 publications

(17 citation statements)

References 32 publications

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“…The activities examined were those of allogeneic CTL, LAK, phagocytic macrophage (Fc-dependent) and tumoricidal macrophage. Several of these activities have been shown previously to be modified by PGE2 and/or indomethacin [2,3,22,24,35,40] …”

Section: Effect Of In Vitro Indomethacin On Host De¢ènse Functions Ofmentioning

confidence: 43%

Indomethacin modulation of Adriamycin-induced effects on multiple cytolytic effector functions

Ehrke

1990

Cancer Immunol Immunother

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The anticancer agent, Adriamycin (ADM), in addition to being a potent cytotoxic drug has been shown to be an effective immunomodulator. This study was undertaken to determine whether ADM-induced changes in the production of prostaglandins (particularly PGE2) are involved in ADM-associated modifications of selected host defenses. Spleen cells from normal or ADM-treated (5 mg/kg; day -5) C57BL/6 mice were assessed for the following activities: fresh (day 0) and cultured natural killer (NK), cytotoxic T lymphocyte, lymphokine-activated killer (LAK), Fc-dependent phagocytosis and tumoricidal macrophage. All activities were assessed with and without the addition of indomethacin, an inhibitor of the first step of the cyclo-oxygenase pathway of prostaglandin synthesis. Depending on culture conditions, the cytotoxic T lymphocyte and splenic tumoricidal macrophage activities were either unaffected or were augmented by ADM treatment of the spleen donor mice or by addition of indomethacin to the culture, and these effects were apparently independent of one another. In contrast, ADM treatment generally resulted in reduced NK and LAK activities relative to control and elevated Fc-dependent phagocytosis. The addition of indomethacin to the culture effectively reversed these effects. Furthermore, spleen cells from ADM-treated mice were found to produce twice the amount of PGE2 in culture compared to cells from untreated mice. Finally, the direct addition of PGE2 to NK cultures resulted in a dose-dependent inhibition of NK activity and the dose required was comparable to the amount of PGE2 produced by cultured spleen cells from ADM-treated mice. Taken together, these results indicate that at least some of the immunomodulatory effects of ADM are an indirect result of ADM-induced changes in PGE2 production.

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Section: Effect Of In Vitro Indomethacin On Host De¢ènse Functions Ofmentioning

confidence: 43%

Indomethacin modulation of Adriamycin-induced effects on multiple cytolytic effector functions

Ehrke

1990

Cancer Immunol Immunother

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“…It was demonstrated that rat hepatocytes suppress the natural cytotoxicity of nonparenchymal liver cells (NPCs) against YAC-1 lymphoma and P815 plasmacytoma cells (17). More recently, we reported that murine hepatic lymphokine-activated-killer cell generation in uitro was markedly inhibited by hepatocytes and liver cytosolic extract (LEx), which appeared to suppress the early phase of interleukin (IL) 2-induced lymphocyte transformation (18). Furthermore, supplementation of the culture medium with up to 5 mmol/L arginine could only partially reverse the inhibitory activity of LEx.…”

supporting

confidence: 40%

“…Independently, Chisari et al (11) identified two hepatic immunoregulatory molecules from rat liver perfusate, L-arginase released by injured hepatocytes and very-lowdensity lipoprotein (VLDL) secreted by intact hepatocytes. Several less-well-characterized factors have also been shown to possess imrnunoinhibitory activityWe have studied the role of parenchymal liver cells (hepatocytes) on hepatic immune responses (17,18). It was demonstrated that rat hepatocytes suppress the natural cytotoxicity of nonparenchymal liver cells (NPCs) against YAC-1 lymphoma and P815 plasmacytoma cells (17).…”

supporting

confidence: 39%

Isolation and characterization of a novel liver-derived immunoinhibitory factor

et al. 1991

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Cytosolic extracts prepared from perfused whole liver or purified hepatocytes of C57BL/6 mice inhibited interleukin-2--and concanavalin A--induced spleen cell proliferation in vitro. In contrast, cytosolic extracts from purified nonparenchymal liver cells had no effect. Arginase and very-low-density lipoprotein were previously identified as two immuninhibitory substances present in liver cytosolic extracts. We demonstrated, however, that inhibitory activity remained after removal of very-low-density lipoprotein and arginase from liver cytosolic extract by repeated ultracentrifugation and gel filtration chromatography, respectively, suggesting the presence of another inhibitor. Further purification by anion-exchange chromatography and chromatofocusing led to the isolation of a novel liver-derived immunohibitory factor. This liver-derived immunoinhibitory factor is sensitive to pronase digestion and heat and acid treatment; it has an estimated isoelectric point of 8.25. The Mr of liver-derived immunoinhibitory factor is 28 kD as estimated from its migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, which is identical under both reducing and nonreducing conditions, indicating a monomeric nature of this protein. Amino acid composition analysis discloses that liver-derived immunoinhibitory factor is relatively rich in glycine and proline residues. Interleukin-2--induced spleen cell proliferation in vitro is inhibited by ths liver-derived immunoinhibitory factor, with a 50% inhibitory dose of 1.4 nmol/L. Furthermore, the biological activity of the liver-derived immunoinhibitory factor is not confined to mouse spleen cells, since the growth of B16 mouse melanoma and H35 rat hepatoma cells is also inhibited. A comparison with other liver-derived immunoinhibitors reported previously supports our claim that the liver-derived immunoinhibitory factor is a novel inhibitory protein.

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“…As previously reported by us [24,27], murine Kupffer cells, when placed in tissue-culture medium in the absence of such stimulators as LPS and IFN 7, produced substantial amounts of IFN~B, which was not detected with splenic macrophages, perito-neal macrophages and blood monocytes under the same experimental conditions. We have further shown that induction of lymphokine-activated-killer (LAK) activity from nonparenchymal liver cells (NPC) was suppressed by this endogenous IFN~/[3 produced specifically by Kupffer cells [27].…”

Section: Lntroductionmentioning

confidence: 44%

“…Past observations by us [1,24,27] and other investigators [4,11,26] have demonstrated the differences in both functional and biochemical characteristics between several macrophage populations including liver macrophages (Kupffer cells), peritoneal macrophages, splenic macrophages, alveolar macrophages and blood monocytes. For instance, Kupffer cells, which play a major role in clearing gut-derived antigens and microbial products, have been shown to display several times more phagocytic activity than peritoneal macrophages [11].…”

Section: Lntroductionmentioning

confidence: 45%

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

Tzung

Cohen

1991

Cancer Immunol Immunother

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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.

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Suppression of hepatic lymphokine-activated killer cell induction by murine kupffer cells and hepatocytes

Cited by 15 publications

References 32 publications

Indomethacin modulation of Adriamycin-induced effects on multiple cytolytic effector functions

Indomethacin modulation of Adriamycin-induced effects on multiple cytolytic effector functions

Isolation and characterization of a novel liver-derived immunoinhibitory factor

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

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