Carlos Feleder

SIGNALING THE BRAIN IN SYSTEMIC INFLAMMATION: THE ROLE OF COMPLEMENT

The complement (C) cascade is activated in almost immediate reaction to the appearance in the body of pathogenic microorganims and their products, e.g., bacterial endotoxic lipopolysaccharide (LPS), resulting in the generation of a series of potent bioactive fragments that have critical roles in the innate immune response of the afflicted host, including, potentially, the production of the fever that so characteristically marks bacterial infections. For instance, its derivatives C3a, C3b, iC3b, C5a, and C5b-9 independently induce the production by myeloid and non-myeloid cells of the cytokines interleukin (IL)-1(, IL-6 and tumor necrosis factor-(, and of prostaglandin (PG)E2, all putative mediators of fever. Therefore, any one of these C components could be involved, centrally or peripherally, in the induction of the febrile response to LPS. Indeed, we have shown that hypocomplementation by cobra venom factor (CVF) dose-dependently attenuates LPS-induced fever in guinea pigs and wild-type (WT) mice, and that C5 gene-ablated mice are unable to develop fever after LPS. In further studies, we found that a specific antagonist to the C5a receptor, C5aR1a, prevents the LPS-induced febrile rise of WT and C3 null mutant mice, implicating C5a as the responsible factor. Various lines of evidence from our laboratory suggest that the macrophages of the liver (Kupffer cells [Kc]) may be the specific target cells of C5a and that the product they release may be PGE2. PGE2, in turn, may be the substance that binds to vagal afferents in the liver that convey the pyrogenic message to the brain. Other studies by our group (not included in this review) have separately traced the neural pathway by which this message may be transmitted from the liver to the brain and processed there for action. The purpose of this article is to review the studies that have led us to conclude that C5a, Kc and Kc-generated PGE2 may be integrally involved in the pathogenesis of LPS fever. If further verified, these results will be important for better understanding how infectious stimuli may trigger the multivariate acute-phase responses generally, and fever particularly, that promptly spring into action to defend the continued well-being of the afflicted host.

Food deprivation alters thermoregulatory responses to lipopolysaccharide by enhancing cryogenic inflammatory signaling via prostaglandin D2

We tested the hypothesis that food deprivation alters body temperature (T(b)) responses to bacterial LPS by enhancing inflammatory signaling that decreases T(b) (cryogenic signaling) rather than by suppressing inflammatory signaling that increases T(b) (febrigenic signaling). Free-feeding or food-deprived (24 h) rats received LPS at doses (500 and 2,500 microg/kg iv) that are high enough to activate both febrigenic and cryogenic signaling. At these doses, LPS caused fever in rats at an ambient temperature of 30 degrees C, but produced hypothermia at an ambient temperature of 22 degrees C. Whereas food deprivation had little effect on LPS fever, it enhanced LPS hypothermia, an effect that was particularly pronounced in rats injected with the higher LPS dose. Enhancement of hypothermia was not due to thermogenic incapacity, since food-deprived rats were fully capable of raising T(b) in response to the thermogenic drug CL316,243 (1 mg/kg iv). Neither was enhancement of hypothermia associated with altered plasma levels of cytokines (TNF-alpha, IL-1beta, and IL-6) or with reduced levels of an anti-inflammatory hormone (corticosterone). The levels of PGD(2) and PGE(2) during LPS hypothermia were augmented by food deprivation, although the ratio between them remained unchanged. Food deprivation, however, selectively enhanced the responsiveness of rats to the cryogenic action of PGD(2) (100 ng icv) without altering the responsiveness to febrigenic PGE(2) (100 ng icv). These findings support our hypothesis and indicate that cryogenic signaling via PGD(2) underlies enhancement of LPS hypothermia by food deprivation.