Tumor necrosis factor infusions in humans prime neutrophils for hypochlorous acid production

Five cancer patients undergoing intravenous infusions of human recombinant tumor necrosis factor (TNF)α were evaluated for the effects these infusions had on the priming of circulating neutrophils for hypochlorous acid (HOCl) production. These patients were also studied for changes in temperature, circulating white blood cell counts, blood pressure, and spontaneous monocyte interleukin 1β (IL-1β) and TNF production. As predicted by previous in vitro studies, patient neutrophils increased their HOCl production to unopsonized zymosan from a baseline of 29.2 ± 5.9 nmol I^- oxidized/4 x 10⁶ cells to a peak of 64.2 ± 9.8 nmol I^- oxidized/4 x 10⁶ cells at 4 h after TNF infusion (P < 0.01). Similar increases were also seen at 4 h with phorbol myristic acetate and opsonized zymosan as the stimuli. The priming effect could be reproduced in neutrophils from a normal individual by incubating them with the 30-min serum samples from the infused patients. The ability of this serum to prime neutrophils was completely blocked by a monoclonal anti-TNF α-antibody but not by an anti-IL-1β antibody. In addition to the priming of their neutrophils, patients also experienced fever, marked hypotension, and an initial fall, followed by rebound to an elevation, in circulating white blood cell counts. The TNF infusions did not produce detectable circulating IL-1β nor did they induce significant production of TNF or IL-1β by circulating blood monocytes. These studies confirm the role of TNF in producing the signs of sepsis such as hypotension, fever, and leukopenia followed by leukocytosis. Furthermore, circulating TNF primes neutrophils in vivo for HOCl production that may represent one of the mechanisms whereby sepsis can induce organ injury.