Induction of endotoxin tolerance in rat bone marrow cells by in vivo infusion of tumor necrosis factor

OBJECTIVETo determine in a rat model whether a low-dose infusion of tumor necrosis factor (TNF) affects the production of the inflammatory cytokines TNF and interleukin (IL)-6, the immunosuppressive factor prostaglandin E2 (PGE2), and complement component C3 (C3) by isolated bone marrow-adherent and -nonadherent cells, cultured in the presence of lipopolysaccharide, a component of bacterial endotoxin. DESIGNRandomized, controlled animal study. SETTINGResearch laboratory of a university medical center. SUBJECTSSprague-Dawley rats (n = 18), 250 to 275 g. INTERVENTIONSAnimals received a continuous infusion of one of the following three treatments for 4 daysa) TNF in saline containing bovine serum albumin; b) saline containing bovine serum albumin; and c) saline alone. MEASUREMENTS AND MAIN RESULTSAfter infusion, isolated bone marrow cells were cultured for 1 day and 3 days, with and without lipopolysaccharide (1 micro g/mL); culture supernatants were assayed for TNF, IL-6, PGE2, and C3. TNF infusion caused a decrease in the in vitro production of TNF, IL-6, and PGE2 by the lipopolysaccharide-stimulated adherent and nonadherent bone marrow cells. This tolerance to lipopolysaccharide stimulation was present after both 1 day and 3 days of culture. TNF infusion caused an increase in C3 production by the nonadherent cells. The production of TNF by adherent cells from saline-infused or bovine serum albumin-infused animals (controls) was greater in 3-day cultures compared with 1-day cultures, whereas the production of IL-6 and PGE2 was less. CONCLUSIONSThese results indicate that TNF infusion caused cells in the bone marrow to be tolerant to lipopolysaccharide stimulation or that TNF infusion programmed the cells to become tolerant to lipopolysaccharide stimulation on differentiation and/or maturation. The results also indicate that bone marrow cells may be regulated by TNF (probably indirectly) at different phases of maturation and/or differentiation with respect to the production of different mediators. Although TNF is considered to be an inflammatory cytokine, at low concentrations it may be an important down-regulator of the inflammatory response. (Crit Care Med 1997; 25:827-833)