Fever and acute phase response induced in rabbits by human recombinant interferon‐gamma.

Abstract

SUMMARY1. Intravenous (i.v.) and intracerebroventricular (I.c.v.) injections of human recombinant interferon-y (IFN-y) produced dose-dependent fevers in rabbits. The fever induced by i.v. injection was monophasic and the maximum elevation occurred 80-110 min after injection. The fever induced by i.c.v. injection was observed from about 20 min after injection and was remarkably prolonged over 4 h.2. The development of pyrogenic tolerance to IFN-y was observed when rabbits were given i.v. injections on 3 successive days. Furthermore, the pyrogenicity of IFN-y was significantly attenuated by heating at 60 'C for 40 min. The i.v. injection of IFN-y enhanced the febrile response induced by endotoxin but had no effect on that induced by endogenous pyrogen.3. The i.v. injection of a large dose of IFN-y (6 x 106 units/kg) induced an acute phase response, which included a reduction in plasma concentration of iron and zinc.4. The present results suggest that IFN-y released from lymphocytes is one of the endogenous mediator proteins responsible for producing fever and acute phase response.

Role of Hypoxia-inducible Factor-1 in Transcriptional Activation of Ceruloplasmin by Iron Deficiency

“…Our findings are consistent with many reports that plasma Cp (and copper) is elevated during multiple conditions of anemia including dietary iron deficiency (18,19), hemorrhage (20), sickle cell disease (21), renal failure (22), pregnancy (26), and anemia of inflammation (23)(24)(25). The importance of HIF-1 activation in transcriptional regulation of liver Cp synthesis would suggest that pathological conditions featuring chronic hypoxia will also activate HIF-1 and thus should increase serum Cp.…”

“…Similar observations have been made in humans: elevated levels of serum copper are observed in anemia due to massive hemorrhage (13), dietary iron deficiency (14), infection or inflammation (15), and pregnancy (16). After the discovery that Cp is the primary copper protein in blood (17), the increase in serum copper was shown to be due to elevated serum Cp in dietary iron deficiency anemia (18,19), hemorrhagic anemia (20), sickle cell disease (21), renal failure (22), anemia of inflammation (23)(24)(25), and anemia associated with pregnancy (26). Whereas the Cp increase in anemia due to pregnancy and inflammation may be influenced by hormone and cytokine levels, the observations on dietary anemia and hemorrhage provide evidence for a direct relationship between iron deficiency and plasma Cp levels.…”

Brain regions involved in the development of acute phase responses accompanying fever in rabbits.

“…Cerami. Figari, Palladino & O'Connor, 1986;Morimoto, Murakami, Takada, Teshirogi & Watanabe, 1987;Morimoto et al 1989). Accordingly, it remains uncertain whether the effects of injecting partially purified EP have been due entirely to the actions of IL-t or whether other cytokines, acting singly or in concert, have contributed to the observed effect.…”

A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment

“…The mechanism of the development of tolerance to acute FLS is unclear. Certainly, the phenomenon of pyrogenic tolerance is well known and has been described for exogenously administered pyrogenic cytokines including interferon gamma 10,11 . However, the exact mechanisms remain to be determined.…”

“…Animal studies have demonstrated that intravenous interferon gamma1b produced a monophasic dose-dependent fever in rabbits and that pyrogenic tolerance was observed following three successive daily injections 11 . The mechanism by which injected interferon gamma-1b evokes the acute pattern of fever is unclear.…”