Pyrogenic and thermogenic effects of interleukin 1 beta in the rat

Abstract

Single injections of recombinant human interleukin 1 beta (IL-1 beta) caused large (up to 2 degrees C) and sustained (3 h) increases in body temperature in conscious rats. Intracerebroventricular injections (10-100 ng) were much more effective and elicited greater responses than intravenous injections (0.1-1 microgram). IL-1 beta increased resting oxygen consumption by 25-49% in a dose-dependent manner. The activity of the thermogenic proton conductance pathway in brown adipose tissue (BAT) mitochondria was assessed from purine nucleotide (GDP) binding and was elevated by 40 and 86% 1 h after intravenous (1 microgram) or intracerebroventricular (100 ng) injection of IL-1 beta, respectively. Regional tissue blood flow was determined in anesthetized rats from the distribution of radiolabeled microspheres. Blood flow to liver (hepatic arterial), testes, skin, and white adipose tissue was unaffected by IL-1 beta injection. Blood flow to brain and kidney was increased (142 and 50%) but reduced (58%) to skeletal muscle after intravenous but not intracerebroventricular injection of interleukin. In contrast, blood flow to BAT was markedly elevated after intravenous (288%) or intracerebroventricular (382%) injection of IL-1 beta. Severing the sympathetic nerves supplying the interscapular BAT depot prevented the increase in blood flow. These data indicate that the potent pyrogenic effects of IL-1 beta in the rat are due largely to a central action. Fever is associated with increases in metabolic rate and BAT activity, and these results provide support for the involvement of brown fat in thermogenesis associated with fever.

Expression of interleukin‐1α and interleukin‐1 receptor type I genes in murine brown adipose tissue

“…Intravenous and intracerebroventricular injection of IL-lfl [7,12], similarly as application of TNF-~ [32,33] or IL-6 [34], were shown to increase (unmask) the number of GDP-binding sites of the UCP in BAT mitochondria and stimulate thermogenesis as well as blood flow in BAT. However, these effects occur only during short onset phase of temperature increase [8,9] and result from central, adrenergically mediated effect of pyrogenic cytokines, as documented by increased norepi- nephrine release in BAT [35] and inhibition of cytokine effects by fl-adrenergic antagonists [9,10] or surgical denervation of BAT [10], As indicated by our data, the response of BAT to LPS and to released cytokines is apparently more complex and the initial, sympathetically mediated activation of heat production is followed by a hyperthermia-counteracting mechanism which causes pronounced, but temporary decrease of expression of UCP and LPL genes (Fig.…”

“…In BAT none of these proteins has been detected so far, although the IL-1 pyrogenic activity is also related to BAT function. BAT thermogenesis was activated after IL-lfl treatment [7], and its involvement in LPS-induced fever was described in different species [8][9][10][11]. In these studies, however, only the centrally mediated stimulation of BAT in febrile states has been demonstrated [5,[7][8][9][10][11][12], although it is possible that BAT could be also directly affected by IL-lfl which also modulates the ILlet production in target tissues [13].…”

Gluttony and thermogenesis revisited

“…As with NST and DIT, the febrile response to infection in mammals involves sympathetic activation of BAT thermogenesis. 17 However, the similarities between these different physiological phenomena go further than this since the anorexia and increased heat production following central injection of leptin has been shown to involve the increased expression of IL-1 and is blocked by IL-1 receptor antagonists. 18 Thus, it appears that the regulation of energy balance by leptin utilises the same, or similar mechanisms involved in the febrile response to infection.…”

Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats

“…The proinflammatory cytokine IL-1␤ is a major peripheral mediator of LPS-induced fever, which is known to trigger increases in body temperature via cyclooxygenase-2 (COX-2)-dependent production of PGE 2 in the brain (35). Studies in experimental animals have demonstrated that recombinant IL-1␤, administered either systemically or directly into the brain, induces fever (2,17) and that neutralization of endogenous IL-1␤ attenuates fever (26,32,36). The majority of these neutralization studies were conducted with a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1ra) (37,52,64), which inhibits the action of IL-1 by competing for the IL-1 receptor (16).…”