A pre-formed Pyrogenic Factor Released by Lipopolysaccharide Stimulated Macrophages

[摘要] The aim of this study was to investigate the pyrogenic activity offactor(s) released by rat peritoneal macrophages following a briefstimulation with LPS. The effect of this factor on the number ofcirculating leukocytes and serum Fe, Cu and Zn levels, was alsoevaluated. The possibility that the content of interleukin(IL)-1β, IL-6 and tumour necrosis factor (TNF) in thesupernatant could explain the observations was investigated.Supernatant produced over a period of 1 h by peritoneal macrophages,following a 30 min incubation with LPS at 37°C, wasultrafiltered through a 10 000 MW cut-off Amicon membrane,sterilized, and concentrated 2.5, 5, 10 and 20 times. Theintravenous (i.v.) injection of this supernatant induced aconcentration-dependent fever in rats with a maximal response at 2h. The pyrogenic activity was produced by macrophages elicited withthioglycollate and by resident cells. The supernatants also inducedneutrophilia and reduction in Fe and Zn 6 h after the injection.Absence of activity in boiled supernatants, or supernatants frommacrophages incubated at 4°C with LPS, indicates that LPS wasnot responsible for the activity.In vitrotreatmentwith indomethacin (Indo), dexamethasone (Dex), or cycloheximide(Chx) did not modify the release of pyrogenic activity into thesupernatant or its effects on the reduction in serum metal levels.Although Chx abolished the production of mediator(s) inducingneutrophilia, and Dex reduced the induction of IL-1β, TNF andIL-6, injection of the highest concentration of these cytokinesdetected in the supernatants did not induce fever.Invivotreatment with Dex, but not Indo, abolished the feverinduced by the supernatant. These results suggest that macrophagescontain pre-formed pyrogenic mediator(s), not related to IL-1β,IL-6 or TNF, that acts indirectly and independently ofprostaglandtn. It also seems likely that the pyrogenic activity isrelated to the factor responsible for the reduction of serum Fe andZn levels, but not the neutrophilia.

[学科分类] 生理学与病理学