Mechanisms of Tumor Necrosis Factor Alpha-Induced Lymphopenia, Neutropenia, and Biphasic Neutrophilia: A Study of Lymphocyte Recirculation and Hematologic Interactions of TNFα With Endogenous Mediators of Leukocyte Trafficking

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Abstract
Tumor necrosis factor alpha (TNF) induces lymphopenia, neutropenia, and biphasic neutrophilia after intravenous injection of 3,000 U TNF in Lewis rats. The mechanism of TNF-induced lymphopenia was investigated by means of thoracic duct cannulation. Hourly measurements of lymphocyte recirculation via the thoracic duct failed to reveal any significant decrease in lymphocyte recirculation in TNF-treated vs. control rats, suggesting that a decrease in lymphocyte recirculation through the thoracic duct is not the mechanism for TNF-induced lymphopenia. The mechanism of TNF-induced neutropenia was investigated by administering TNF to rats in whom a neutrophilia had been induced with Interleukin-1 (IL-1). In rats with neutrophilia, TNF resulted in a sharp decrease in the circulating neutrophil pool, demonstrating that TNF induces neutropenia by causing neutrophils to leave the circulating pool rather than decreasing neutrophil release from the marrow. The mechanism of neutropenia was furthermore shown to be due to the transient intravascular margination of neutrophils by administering epinephrine concomitantly with TNF. Epinephrine, which causes neutrophilia solely by demargination, abrogated the TNF-induced neutropenia and actually resulted in a neutrophilia that was greater than the neutrophilia occurring in epinephrine alone-treated rats, demonstrating both that TNF had already caused release of marrow neutrophils at the time of peripheral neutropenia, and that the paradoxical neutropenia was due to the transient intravascular margination of neutrophils. The known property of epinephrine to cause neutrophilia exclusively by demargination was proved by examination of the bone marrow of epinephrine-treated rats in whom no decrease in marrow neutrophils was observed (in contrast to TNF- and IL-1-treated rats in whom neutrophilia is accompanied by a depletion of marrow neutrophils). The mechanism of TNF-induced neutrophilia was investigated by modulating the magnitude of both the first and second peaks of neutrophilia by priming of rats with daily injections of IFNγ for 2 days prior to administration of TNF. The first peak of neutrophilia in IFNγ-primed TNF-treated rats was decreased in comparison to TNF alone-treated rats because of the well-known neutropenic and myelosuppressive effect of IFNγ, which resulted in a decrease in the number of neutrophils that could be recruited to cause neutrophilia. The second peak of neutrophilia in IFNγ-primed TNF-treated rats, however, was increased in relation to the magnitude of the first peak, an observation that is consistent with the known priming effect of IFNγ on macrophages and the concept that the second peak of neutrophilia is due to the release of endogenous monokines. A possible negative feedback role for TNF in contributing to the in vivo regulation of biological responsiveness to TNF itself was tested by administering TNF to C3H/HeJ mice (which are deficient in TNF production but not TNF receptors) and to congenic C3H/HeN mice (which are not deficient in TNF). TNF induced a greater neutropenia and a greater neutrophilia in C3H/HeJ than in C3H/HeN mice, suggesting that a tonic deficiency in TNF results in a hyperresponsive state that might be postulated to represent upregulation of TNF receptors. In conclusion, experimental evidence is presented consistent with the hypotheses that TNF-induced lymphopenia and neutropenia are due to transient intravascular margination, that the second peak of TNF-induced neutrophilia is due to the release of endogenous monokines, and that the state of neutrophil responsiveness to TNF may be regulated by TNF itself by a negative feedback mechanism.