Ceramide mediates the rapid phase of febrile response to IL-1β

Abstract

IL-1␤ was identified after a long search for the endogenous pyrogen. It acts by inducing synthesis of prostaglandin E 2, which mediates the late phase of IL-1␤-induced fever. Here we show by radiotelemetry that the early phase of the fever response to IL-1␤ is mediated by ceramide. Hypothalamic application of the cellpenetrating C2-ceramide mimics the rapid phase of the IL-1␤-induced fever. Inhibition of ceramide synthesis blocks the rapid phase of fever but does not affect the slower prostaglandin E 2-dependent phase, which is blocked by indomethacin or by null mutation of the EP3 prostanoid receptor. Electrophysiological experiments on preoptic area͞anterior hypothalamic neurons show that C2-ceramide, but not dihydroceramide, mimics the rapid hyperpolarizing effects of IL-1␤ on the activity of warm-sensitive hypothalamic neurons. IL-1␤-mediated hyperpolarization is blocked by PP2, the selective inhibitor of the protein tyrosine kinase Src, which is known to be activated by ceramide. These in vivo and in vitro data suggest that ceramide fulfills the criteria for an endogenous pyrogen.fever ͉ neutral sphingomyelinase ͉ preoptic area A multitude of microbial and inorganic substances of widely varying origin and chemical composition are able to cause fever, a regulated rise in core body temperature (CBT) (1, 2). Root and Wolff (3) have pointed out that the uniformity of the fever response to all of these pyrogens, with respect to peak temperature and duration, suggests there may be an endogenous common mediator, an endogenous pyrogen. A long search has identified IL-1 as the endogenous pyrogen that mediates the common action of a broad variety of exogenous substances (4). Another line of investigation for the endogenous pyrogens was based on the pharmacological identification of antipyretic substances such as salicylates more than a century ago. Because this class of antipyretic agents are effective in reducing fever of almost any cause, it was implied there must exist an endogenous pyrogen whose synthesis and͞or effects are blocked by salicylates. Experiments with purified and later with recombinant IL-1␤ showed that indeed the fever response to LPS, an exogenous pyrogen from Gram-negative bacteria wall, was mimicked by IL-1␤ (reviewed in ref. 1) and blocked by salicylates (5). The identification of prostaglandin (PG) E 2 (PGE2) as another endogenous pyrogen and the recognition of the role of salicylates and aspirin-like antiinflammatory drugs as inhibitors of PG biosynthesis have produced a working hypothesis for the fever response to Gram-negative bacteria: Bacterial cell wall 3 LPS 3 IL-1␤ 3 cyclooxygenase (COX)2 3 PGE2 3 fever response.This cascade also provided an explanation for the antipyretic effects of PG synthesis inhibitors. Subsequent studies using null mutated mice strains for prostanoid receptor subtypes, as well as selective drugs for prostanoid receptors, identified the EP3 prostanoid receptor (EP3R) and EP1R receptors as mediators of the pyrogenic effects of PGE2 (6-9). This scheme has been usefu...

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

“…This is mediated by the activation of Src family protein tyrosine kinases, which is effected by neutral sphingomyelinase-generated ceramides. The activation of neutral sphingomyelinase involves the recruitment of the scaffolding protein MyD88 to the agonist-charged IL-1 receptor complex [60]. In the present study, we observed the involvement of ceramide in IL-1β-mediated suppression of BDNF signaling.…”

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

“…There are at least five types of Smases, including the ubiquitous lysosomal acid SMase, the zinc-dependent secreted acid SMase, a neutral, Mg 2+ -dependent SMase, a neutral Mg 2+ -independent SMase, and an alkaline SMase. Neutral sphingomyelinase 2 (nSMase2) is a brain-specific nSMase that is thought to be located on the inner leaflet of the plasma membrane and is activated by phosphatidylserine and cellular stressors including the inflammatory cytokines TNFα, IL-1, Fas-L, UV irradiation, the neurotoxic HIV-proteins gp120 and Tat, and amyloid β (Brann et al 1999;Sortino et al 1999;Haughey et al 2003;Castiglione et al 2004;Lee et al 2004;Sanchez-Alavez et al 2006). Once nSMase2 is active, sphingomyelin shifts to the innerleaflet of the plasma membrane, where it can be catabolized to ceramide.…”

Histaminergic Modulation of Body Temperature and Energy Expenditure

“…The thermosensitivity of PO/AH neurons is a plastic property both in vivo and in vitro. It has been found that the thermosensitivity can change rapidly in the presence of the pyrogens PGE2 [4] or IL-1 [5,6]. Slower changes are observed in some warm-sensitive PO/AH neurons which decrease their thermosensitivity during NREM sleep [7].…”

“…We have shown that prostaglandin E2 (PGE2), a well established endogenous pyrogen, increases the thermosensitivity and firing rates of PO/AH neurons by decreasing the frequency of IPSPs [4]. In contrast, IL-1β hyperpolarizes a different set of PO/AH neurons and reduces their thermosensitivity by increasing the frequency of IPSPs and of miniature IPSPs [5,13].…”

“…Preoptic warming, glutamate injections as well as electrical stimulation facilitate salivary secretion [5,13,15] as well as body extension [24], another aspect of evaporative heat loss.…”