Mouihate Abdeslam, Boissé Lysa, Pittman Quentin J
Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Alberta, T2N 4N1 Canada.
J Neurosci. 2004 Feb 11;24(6):1312-8. doi: 10.1523/JNEUROSCI.3145-03.2004.
Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.
发热是宿主防御反应的重要组成部分，但如果不受控制，发热可能有害。我们提供了首个证据，表明15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2），一种过氧化物酶体增殖物激活受体γ（PPARγ）的内源性配体，可通过作用于大脑减弱大鼠对脂多糖（LPS）的发热反应。此外，我们表明PPARγ在下丘脑中表达，下丘脑是大脑中发热产生的重要部位。另外，15d-PGJ2及其合成酶（PGD2合酶）存在于大鼠脑脊液中，并且它们的水平在全身注射LPS后升高。15d-PGJ2的解热作用与LPS刺激的下丘脑环氧化酶-2表达降低有关，但与p44/p42丝裂原活化蛋白激酶磷酸化或PPARγ的表达无关。因此，大脑中可能存在一条内源性前列腺素途径的平行诱导，能够限制促炎前列腺素E2依赖性途径的有害作用。
