title: Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes.
abstract: Human recombinant interleukins 1 alpha and 1 beta (rIL-1 alpha and -1 beta) both induced monophasic peripheral neutrophilia and lymphopenia in Lewis rats 1.5 hr after i.v. injection. The kinetics of rIL-1 alpha- and -1 beta-induced neutrophilia were similar to those induced by human monocyte-derived IL-1, IL-1 alpha, and IL-1 beta, and the peripheral neutrophilia was accompanied by a marked decrease in marrow neutrophils. Arachidonic acid metabolites are implicated as biochemical intermediates in the production of the neutrophilia but not lymphopenia, since indomethacin and dexamethasone both completely abrogated IL-1-induced neutrophilia but did not affect the IL-1-induced lymphopenia. Acetylsalicylic acid, a cyclooxygenase inhibitor, did not inhibit IL-1-induced neutrophilia, suggesting that products of the lipoxygenase rather than the cyclooxygenase pathway of arachidonate metabolism may contribute to the neutrophilia. Human recombinant tumor necrosis factor-alpha (rTNF) administered i.v. to Lewis rats induced peripheral neutropenia, two peaks of neutrophilia, and lymphopenia. A wide range of doses of rTNF resulted in an initial neutropenia at 0.5 hr after injection followed by a first peak of neutrophilia at 1.5 hr and a second peak of neutrophilia at 6 hr. The initial neutropenia and the first peak of neutrophilia were not inhibited by pretreatment of rats with dexamethasone, indomethacin, or aspirin. The second peak of neutrophilia was inhibited by both dexamethasone and indomethacin, but was not at all inhibited by aspirin, suggesting that the second peak of neutrophilia is mediated by the release of endogenous cytokines, especially by IL-1, since exogenous IL-1-induced neutrophilia is also completely inhibited by dexamethasone and indomethacin but not by aspirin. The TNF-induced peripheral neutrophilia is also accompanied by a significant depletion of bone marrow neutrophils, indicating that the source of increased circulating neutrophils is, at least in part, via recruitment of marrow neutrophils. Systemic blood pressure was not affected by IL-1 or rTNF at the dosages employed, showing that the changes in circulating leukocyte subsets were not attributable to hemodynamic changes nor to the hemodynamic change-related release of adrenal hormones. Adrenalectomy did not alter the IL-1- or rTNF-induced neutrophilia or lymphopenia, also demonstrating that neither monokine mediates its hematologic effects on peripheral blood leukocytes via the release of adrenal hormones.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pathology, University of California, Irvine 92717.
authors.forename: T R
authors.initials: TR
authors.lastname: Ulich
authors.forename: J
authors.initials: J
authors.lastname: del Castillo
authors.forename: M
authors.initials: M
authors.lastname: Keys
authors.forename: G A
authors.initials: GA
authors.lastname: Granger
authors.forename: R X
authors.initials: RX
authors.lastname: Ni
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001688:Biological Products / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines; D003907:Dexamethasone / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000302:isolation & purification / Q000633:toxicity*; D007700:Kinetics; D007958:Leukocyte Count; D007964:Leukocytosis / Q000139:chemically induced* / Q000503:physiopathology; D008231:Lymphopenia / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009000:Monocytes / Q000032:analysis; D009504:Neutrophils; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D001095:Arachidonic Acids; D001688:Biological Products; D016207:Cytokines; D007375:Interleukin-1; D011448:Prostaglandin Antagonists; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone