A review of the physiology of fever in birds.

While fever is known to occur in invertebrates and vertebrates, the mechanisms of fever in animals other than mammals have received scant attention. We look initially at the recognition, by the avian immune system, of pathogen associated molecular patterns and the likely role of toll-like receptors in signaling the presence of bacteria and viruses. Several mediators of fever are subsequently released by immune cells, including interleukin-6 and interleukin-1ß, that eventually reach the brain and alter thermoregulatory function. As is the case in mammals, prostaglandins appear to be the ultimate mediators of fever in birds, since the febrile response is attenuated when prostaglandin synthesis is inhibited. Ambient temperature modulates the fever response, with larger fevers at higher, and smaller fevers at lower ambient temperatures. Glucocorticoid levels are increased during fever and seem to play an important role by modulating the extent of fever generation, possibly playing a role in the attenuation of fever after repeated exposure to a pathogen in a process termed tolerance, suggesting that the fever process can be phenotypically adapted to likely future conditions. While fever has an ancient phylogenetic history and many of the underling mechanisms in birds appear similar to mammals, there are several important differences that suggest fever has evolved quite differently in these two homeothermic classes.

The development of endotoxin tolerance, and the role of hypothalamo-pituitary-adrenal function and glucocorticoids in Pekin ducks.

Endotoxin tolerance represents a state of abated immunological responsiveness to pyrogens, which, in mammals, leads to the decline or abolition of the fever response. The development of endotoxin tolerance in birds is not well understood; consequently, the impact of repeated pathogenic exposure on the avian febrile response, and thus on the ability of birds to fight recurrent infection, is not known. We determined the effect of repeated injections of lipopolysaccharide (LPS) on the febrile response of Pekin ducks. We gave ducks five injections of LPS, spaced 1, 4 or 10 days apart, and recorded their core body temperature with abdominally implanted temperature data loggers. Once we established that Pekin ducks developed endotoxin tolerance, we investigated the effect of repeated injections of LPS on the central and peripheral segments of the hypothalamo-pituitary-adrenal (HPA) axis in an attempt to elucidate the role of glucocorticoids in the modulation of the febrile response during the tolerant period. When our ducks became tolerant to LPS, they had significantly higher basal levels of plasma corticosterone (CORT, the principal glucocorticoid in birds), and their HPA response to treatment with LPS was blunted. We propose that the augmented levels of basal plasma CORT resulted from sensitized HPA function, and this, in turn, contributed to the development of endotoxin tolerance. Regulation of the circulating level of CORT might be a possible target for the re-establishment of appropriate immune responses in birds.

Brain IL-6- and PG-dependent actions of IL-1ß and lipopolysaccharide in avian fever.

There is no persuasive evidence of a correlation between proinflammatory cytokines and avian fever. In this study, for the first time, we use avian cytokines to investigate a role for proinflammatory cytokines in the central component of avian fever. IL-1ß and IL-6 injected intracerebroventricularly into Pekin ducks (n = 8) initiated robust fevers of equal magnitude and duration, although there was a significant difference in the latency to a febrile response. In addition, the IL-1ß-induced fever could be abolished with an intracerebroventricular injection of antibodies to avian IL-6 or an oral administration of a PG synthesis inhibitor. Our findings indicate the following sequence of events within the central component of the avian febrile mechanism: IL-1ß gives rise to bioactive IL-6, which stimulates an accelerated synthesis of PGs, and these PGs then adjust the sensitivity of warm-sensitive neurons in the avian brain stem to mediate fever. Yet PGE2 was not upregulated in the cerebrospinal fluid of ducks made febrile with LPS. We conclude that IL-1ß and IL-6 may well mediate fever by instigating an accelerated synthesis of brain-derived PG, of a class other than PGE2, or that IL-6 serves as one of the terminal mediators of the avian febrile response.

A role for natriuretic peptide in lipopolysaccharide-induced fever in Pekin ducks (Anas platyrhynchos): is natriuretic peptide an endogenous antipyretic in birds?

The febrile mechanism in all vertebrates involves endogenous molecules which mediate and attenuate the fever response. This mechanism is considered phylogenetically conserved, and the molecules are thought to be analogous in different species. The above notion is supported by evidence which show avian and mammalian fevers to have similar mediators. There is, however, a paucity of information regarding the modulators of the avian febrile response. Natriuretic peptides were shown to modulate mammalian fevers and, although natriuretic peptides are also present in birds, they have never been investigated in the context of fever. We induced fever in Pekin ducks with lipopolysaccharide and, at the same time, treated the animals with natriuretic peptide antiserum at a dose that effectively inhibited the known renal actions of endogenously secreted natriuretic peptide. We compared fever responses after ducks received either the antiserum or an appropriate control along with the lipopolysaccharide. The antiserum did not attenuate the fever responses of ducks. Our results differ from the results of a study in rats, which demonstrated natriuretic peptides to be potently antipyretic. This molecule seems to be antipyretic in mammals but not in ducks. We suggest a species variation regarding the ability of natriuretic peptides to modulate fever.