Studies on the Origin of Human Leukocytic Pyrogen

Abstract

Granulocytes and monocytes derived from inflammatory exudates or the peripheral circulation of several mammalian species (1-5) can be stimulated to release a pyrogen, leukocytic pyrogen (LP) 1, which induces a characteristic febrile response in rabbits. Chemical characterization of LP has shown it to be a protein molecule (6-8) and since the original discovery of its production by rabbit peritoneal exudate cells (9), many attempts have been made to determine the mechanism of its synthesis by leukocytes. With one exception (10), preformed pyrogen has not been obtained from disrupted rabbit cells (11,12). Its release in vitro has been shown to take place over a several hour period (4, 11, 12), to be dependent upon the temperature of incubation (11), and inhibited by agents which bind sulfhydryl groups in enzymes (13). These findings suggest that LP is either synthesized de novo or activated from a precursor substance after contact with an appropriate stimulating agent.In the present studies, the role of RNA and protein synthesis and the energy requirements for pyrogen release by human peripheral leukocytes activated by the ingestion of heat-killed bacteria have been investigated. The results reported here indicate that both transcription of messenger RNA and its translation by ribosomes into

Studies on the Pathogenesis of Fever

“…Actinomycin D also inhibits activation of blood leukocytes stimulated by endotoxin. Similar findings have been obtained by Bodel, et al (11) with activation by phagocytosis and by etiocholanolone, and by Nordland et al (12) with activation by phagocytosis and by endotoxin. When, on the other hand, exudate leukocytes or activated blood leukocytes (see Tables X and XII) are incubated in 0.15 M NaC1, pyrogen production is not influenced by inhibitors of protein synthesis (9,11), since the cells have already been activated.…”

“…Exudate.--To study the in vivo conditions that accompany the accumulation of detectable amounts of pyrogen in acute peritoneal exudates, rabbits were injected intraperitoneally in the usual manner with 400 ml of glycogen-sMine (7) and were sacrificed at intervals of 1,4,8,12, and 18 hr. The results of the analyses performed at each interval are summarized in Table I.…”

Heat-shock protein synthesis by human polymorphonuclear cells.

“…Response to various temperatures, as well as the time course of induction were assessed. Exposure to 40°C for [1][2][3][4][5] h resulted in no HSP synthesis, Exposure to 41°C for 1 h resulted in moderate HSP synthesis, which was maintained after 2 h of continuous exposure, but was reduced to base-line levels after 3 h at the elevated temperature . Maximal HSP synthesis was induced when cells were exposed to 42-43°C .…”

The Production of Antibody against Human Leukocytic Pyrogen

“…The use of inhibitors of mRNA and protein synthesis has provided indirect evidence that human LP is a newly synthesized protein (19). This conclusion is based on the ability of these inhibitors to prevent formation of biologically active LP.…”