Systemic
inflammation is accompanied by changes in body temperature, either
fever or
hypothermia. Over the past decade, the rat and mouse have become the predominant animal models, and new species-specific tools (recombinant
antibodies and other
proteins) and genetic manipulations have been applied to study
fever and
hypothermia. Remarkable progress has been achieved. It has been established that the same inflammatory agent can induce either
fever or
hypothermia, depending on several factors. It has also been established that experimental
fevers are generally polyphasic, and that different mechanisms underlie different febrile phases. Signaling mechanisms of the most common
pyrogen used, bacterial
lipopolysaccharide (LPS), have been found to involve the
Toll-like receptor 4. The roles of
cytokines (such as
interleukins-1beta and 6 and
tumor necrosis factor-alpha) have been further detailed, and new early mediators (e.g.,
complement factor 5a and
platelet-activating factor) have been proposed. Our understanding of how peripheral inflammatory messengers cross the blood-brain barrier (BBB) has changed. The view that the organum vasculosum of the lamina terminalis is the major port of entry for pyrogenic
cytokines has lost its dominant position. The vagal theory has emerged and then fallen. Consensus has been reached that the BBB is not a divider preventing signal transduction, but rather the transducer itself. In the endothelial and perivascular cells of the BBB, upstream signaling molecules (e.g., pro-inflammatory
cytokines) are switched to a downstream mediator,
prostaglandin (PG) E2. An indispensable role of
PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing
enzymes or
PGE2 receptors. The PGE2-synthesizing
enzymes include numerous
phospholipases (PL) A2,
cyclooxygenases (COX)-1 and 2, and several newly discovered terminal
PGE synthases (PGES). It has been realized that the "physiological," low-scale production of
PGE2 and the accelerated synthesis of
PGE2 in
inflammation are catalyzed by different sets of these
enzymes. The "inflammatory" set includes several
isoforms of PLA2 and inducible
isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The
PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "
fever receptor." The effector pathways of
fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vaso-constriction are located. The rapid progress in our understanding of how thermoeffectors are controlled has revealed the inadequacy of set point-based definitions of thermoregulatory responses. New definitions (offered in this review) are based on the idea of balance of active and passive processes and use the term balance point. Inflammatory signaling and thermoeffector pathways involved in
fever and
hypothermia are modulated by
neuropeptides and
peptide hormones. Roles for several "new"
peptides (e.g.,
leptin and
orexins) have been proposed. Roles for several "old"
peptides (e.g.,
arginine vasopressin,
angiotensin II, and
cholecystokinin) have been detailed or revised. New pharmacological tools to treat
fevers (i.e., selective inhibitors of COX-2) have been rapidly introduced into clinical practice, but have not become magic bullets and appeared to have severe side effects. Several new targets for
antipyretic therapy, including mPGES-1, have been identified.