IL-1␤ has been proposed to be an important mediator linking infection, apnea, and sudden infant death syndrome. We hypothesized that IL-1␤ acts in this capacity by depressing brainstem respiratory neurons via a prostaglandin-dependent pathway. For studying the effects of IL-1␤ on respiration as well as the mechanism underlying its actions, 7-d-old rats received an initial injection (i.p.) of NaCl or a cyclooxygenase inhibitor (indomethacin, 10 mg/kg) followed by a second injection (i.p.) at 30 min of NaCl, recombinant rat IL-1␤ (10 g/kg), or lipopolysaccharide (LPS; 100 g/kg). Respiration during normoxia and in response to anoxia (100% N 2 ) was examined at 60 min after the second injection using flow and barometric plethysmography. Animals given IL-1␤ breathed more slowly and died more often after anoxia. LPS also reduced the rats' ability to autoresuscitate and survive an anoxic challenge. Indomethacin prevented the depressive effects during normoxia and the adverse effects on survival. For investigating drug-induced changes in central respiratory activity, IL-1␤ (1.0 or 1.25 ng/mL) and prostaglandin E 2 (5 or 20 g/L) was applied to the brainstem-spinal cord preparation of 0-to 4-d-old rats. Whereas IL-1␤ exerted no effect on respiration measured at the C4 ventral root during a 60-min period, prostaglandin E 2 reversibly inhibited respiratory activity. These findings suggest that IL-1␤ does not inhibit respiratory neurons directly but may depress breathing and hypoxic defense via a prostaglandin-mediated mechanism. Abbreviations BBB, blood-brain barrier COX-2, cyclooxygenase-2 f R , respiratory frequency LPS, lipopolysaccharide NTS, nucleus of the solitary tract PGE 2 , prostaglandin E 2 RVLM, rostral ventrolateral medulla Infection, hypoxia, and apnea each have been implicated in the pathogenesis of sudden infant death syndrome, and it has been postulated that the proinflammatory cytokine IL-1␤ may serve as the critical link between them (1, 2). IL-1␤ is released during an acute-phase immune response and subsequently induces multiple effects within the CNS, including the initiation of fever, sleep, and neuropeptide release [for review, see (3)]. Previous studies indicated that this immunomodulator may also alter respiration and autoresuscitation, yet the mechanism underlying such effects must be further elucidated (4 -7). Systemic administration of IL-1␤ has been shown to induce time-and dose-dependent expression of early immediate genes in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), both of which contain neurons important for respiratory control and the latter houses the central pattern generator for breathing (8,9). Because of its size and lipophilic properties, IL-1␤ does not diffuse readily across the blood-brain barrier (BBB) (10). However, IL-1␤ may still communicate with the brain across the BBB via active transport passage, through circumventricular organs, vagal afferent stimulation, and via second messenger induction at the BBB [for review, see (11)].We propose ...

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