Central Nervous System-Initiated Inflammation and Neurotrophism in Trauma: IL-1β Is Required for the Production of Ciliary Neurotrophic Factor This information is current as of September 25, 2021. Leonie M. Herx, Serge Rivest and V. Wee Yong J Immunol 2000; 165:2232-2239; ; doi: 10.4049/jimmunol.165.4.2232 http://www.jimmunol.org/content/165/4/2232 Downloaded from References This article cites 51 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/165/4/2232.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Central Nervous System-Initiated Inflammation and Neurotrophism in Trauma: IL-1␤ Is Required for the Production of Ciliary Neurotrophic Factor1 Leonie M. Herx,* Serge Rivest,‡ and V. Wee Yong2*† Injury to the CNS results in the production and accumulation of inflammatory cytokines within this tissue. The origin and role of inflammation within the CNS remains controversial. In this paper we demonstrate that an acute trauma to the mouse brain results in the rapid elevation of IL-1␤. This increase is detectable by 15 min after injury and significantly precedes the influx of leukocytes that occurs hours after. To confirm that IL-1␤ up-regulation is initiated by cells within the CNS, in situ hybridization for cytokine transcript was combined with cell type immunohistochemistry. The results reveal parenchymal microglia to be the sole source of IL-1␤ at 3 h postinjury. A role for CNS-initiated inflammation was addressed by examining the expression of the Downloaded from neurotrophic factor, ciliary neurotrophic factor (CNTF). Analysis of their temporal relationship suggests the up-regulation of CNTF by IL-1␤, which was confirmed through three lines of evidence. First, the application of IL-1 receptor antagonist into the lesion site attenuated the up-regulation of CNTF. Second, the examination of corticectomized animals genetically deficient for IL-1␤ found no CNTF up-regulation. Third, the lack of CNTF elevation in IL-1␤ null mice was rescued through exogenous application of IL-1␤ into the lesion site. These findings provide the first evidence of the requirement for IL-1␤ in the production of CNTF following CNS trauma, and suggest that inflammation can have a beneficial impact on the regenerative capacity of the http://www.jimmunol.org/ CNS. The Journal of Immunology, 2000, 165: 2232–2239. he reaction of the CNS to trauma is a predeterminant of ies by Nieto-Sampedro et al. (10) showed that extracts collected the ability of the CNS to recover. From the investigations from sites of brain injury promoted the survival of sympathetic, T of numerous groups, it has become evident that an in- parasympathetic, and sensory neurons in culture. More recent crease in the levels of proinflammatory cytokines is a normal and work has identified these factors to include nerve growth factor early feature of the CNS response to trauma (1–3). In particular, (NGF)3 (11), ciliary neurotrophic factor (CNTF) (12, 13), basic we have shown that IL-1 and TNF-␣ become significantly elevated fibroblast growth factor (13), and insulin-like growth factor-1 (14). within the CNS parenchyma by 3 h after a brain stab wound injury, If this transient release of trophic factors could be prolonged, the by guest on September 25, 2021 and are localized to the lesion site (4). ability of the CNS to recover from injury may be improved. The source of inflammatory cytokines in the CNS following An important step to being able to manipulate the duration and trauma remains unresolved. Infiltrating leukocytes are obvious magnitude of neurotrophic factor activity is to identify the molec- candidates, but the CNS is unlike other organs in that the influx of ular mediators involved in their production. In this regard, the leukocytes is delayed in response to an acute insult. Thus, neutro- relationship between inflammatory cytokines and neurotrophic phils do not infiltrate appreciably until about 6 h after injury, factors, given their similar spatial expression following injury, whereas T cells and monocytes appear between 12 to 24 h or later may be critical. In vitro, a number of reports have shown inflam- (5–9). These results suggest that the CNS mounts an early and matory cytokines to influence the induction of neurotrophic factor intrinsic inflammatory response upon injury, before leukocyte in- production, with much emphasis placed on the induction of NGF filtration occurs. The origin of the early increase in inflammatory by IL-1 (reviewed in Ref. 15). This work has also been carried over cytokines within the CNS following trauma remains unresolved, to an in vivo context in which exogenous administration of IL-1 into although microglia have been suggested as possible sources (2, 3). the brain has resulted in the up-regulation of NGF (16, 17). Another hallmark of CNS injury is the posttrauma transient ex- In contrast, very little work has been done to examine whether pression of neurotrophic factors around the lesion site. Early stud- inflammatory cytokines affect CNTF production. CNTF is of par- ticular interest because, in addition to being a survival factor for various neuronal populations, it has potent effects on cells of the Departments of *Clinical Neurosciences and †Oncology, Faculty of Medicine, Uni- versity of Calgary, Calgary, Alberta, Canada; and ‡Laboratory of Molecular Endo- oligodendroglial lineage (reviewed in Ref. 18). CNTF has been crinology and Department of Anatomy and Physiology, Laval University, Quebec, shown to be an important maturation factor for oligodendrocytes, Canada to promote their synthesis of myelin proteins (19, 20), and to pro- Received for publication April 7, 2000. Accepted for publication June 6, 2000. tect oligodendrocytes from apoptotic death induced by several The costs of publication of this article were defrayed in part by the payment of page agents (19, 21). Thus, the regulation of CNTF expression in the charges. This article must therefore be hereby marked advertisement in accordance CNS following injury may be particularly important for attenuat- with 18 U.S.C. Section 1734 solely to indicate this fact. ing neuronal and oligodendrocyte death. 1 This work was supported by an operating grant from the Medical Research Council of Canada (MRC). V.W.Y. is a Senior Scholar of the Alberta Heritage Foundation for Medical Research (AHFMR) and a MRC Scientist. S.R. is also a MRC Scientist. L.M.H. gratefully acknowledges AHFMR and MRC for studentship support. 2 Address correspondence and reprint requests to Dr. V. Wee Yong, Departments of 3 Abbreviations used in this paper: NGF, nerve growth factor; CNTF, ciliary neuro- Clinical Neurosciences and Oncology, Faculty of Medicine, 3330 Hospital Drive NW, trophic factor; IL-1ra, IL-1 receptor antagonist; ISH, in situ hybridization; ICC, com- Calgary, Alberta T2N 4N1, Canada. E-mail address: [email protected] bined immunocytochemistry; GFAP, glial fibrillary acidic protein. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 2233 The principal aims of this study were to elucidate the earliest inflicted wound was comparatively large, in accordance with previous de- period posttrauma in which elevation of inflammatory cytokines scriptions (23). Following removal of the dura mater, corticectomy was occurs, to define the cell type responsible for the initial elevation performed by aspiration of the cortex just down to the dorsal aspect of the corpus callosum. Recombinant murine IL-1␤ (50, 200, or 1000 U) (R&D of cytokines, and to establish if a causal relationship exists in vivo Systems, Minneapolis, MN), recombinant human IL-1 receptor antagonist between the elevation of inflammatory cytokines and CNTF fol- (IL-1ra; 50 ␮g/ml) (Amgen, Thousand Oaks, CA), or a saline control were lowing CNS corticectomy trauma. administered locally into the lesion site by means of a piece of absorbent gelatin sponge (Gelfoam, Upjohn, Kalamazoo, MI). Gelfoam was cut to ϳ1mm3 dimensions, soaked in a 10 ␮l volume of the test compound, and Materials and Methods applied directly over the corticectomy site for the duration of the experi- Mice ment, as detailed previously (23). All animals were sacrificed by cervical dislocation. Adult retired female breeders (4–6 mo) of the CD1 strain (Charles River, Montreal, Canada), IL-1␤Ϫ/Ϫ mice (129Sv/C57BL6, back-crossed for three generations with the B10RIII strain as previously described) (22), and RT-PCR the B10RIII genetic controls (The Jackson Laboratory, Bar Harbor, ME) The levels of transcripts encoding inflammatory cytokines IL-1␣, IL-1␤, were housed on a 12-h light/dark cycle with ad libitum access to food and and TNF-␣, as well as CNTF and GAPDH, were determined by semiquan- water. All experimental procedures were approved by the institution’s an- titative RT-PCR. Total RNA was isolated from tissue resected from around imal care committee and were in accordance with the guidelines instituted the lesion site (Fig. 1a) using the TRIzol reagent (Life Technologies, Bur- by the Canadian Council of Animal Care. CD1 mice were used in the lington, Ontario).