AUTOREGULATION BY EICOSANOIDS OF HUMAN KUPFFER CELL SECRETORY PRODUCTS - A STUDY OF INTERLEUKIN-1, INTERLEUKIN-6, TUMOR-NECROSIS-FACTOR-ALPHA, TRANSFORMING GROWTH-FACTOR-BETA, AND NITRIC-OXIDE

Objective Methods employed previously to analyze the secretory behavio r of rodent Kupffer cells (KC) were used to examine the human KC's sec retory response to lipopolysaccharide (LPS). Summary Background Data A s the resident hepatic macrophage, the KC resides al the interlace bet ween the portal and systemic circulations. Consequently, this cell may play an integral role in the immune response to antigens and bacteria in the sinusoid. Study of cytokine production by the KC has relied pr edominantly on the rat as the source ct these cells. Whether human KCs respond similarly to rat KCs after LPS stimulation has been a matter of speculation. Methods Kupffer cells obtained from seven human livers were tested under conditions identical to those used to study rat KCs . Kupffer cells rested for 12 hours after isolation were stimulated wi th LPS (2.5 mu g/mL). Arginine concentration in the culture medium var ied from 0.01 to 1.2 mM. To examine the role of eicosanoids, parallel culture wells received indomethacin (10 mu M). Culture supernatants we re assayed for interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necro sis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-bet a), prostaglandin E(2) (PGE(2)), and nitric oxide. Results Similar to the rat KC, LPS-stimulated human KCs released IL-1, IL-6, TNF-alpha, T GF-beta, and PGE(2). However, unlike rat KCs, nitric oxide could not b e detected, regardless of whether the human KCs were exposed to LPS, i nterferon-gamma (INF-gamma), or LPS + IFN-gamma. Similar to rat KCs, i ndomethacin prevented PGE(2) release while significantly upregulating TNF-alpha, IL-1, and IL-6, but not TGF-beta, consistent with an autore gulatory control of eicosanoids over proinflammatory cytokines. As has been shown in the rat, physiologic levels of L-arginine (0.01 mM) sig nificantly enhanced LPS-induced PGE(2) secretion relative to the respo nse in medium containing standard L-arginine concentration (1.2 mM); h owever, unlike the rat KC, the human's cytokine response to LPS was no t downregulated by this enhanced PGE(2) release. Conclusions Although many functional features are shared by rat and human KCs, significant differences do exist. Such discrepancies reinforce the need to proceed with caution when generalizing from the results obtained in other spe cies to human physiology.