0013-7227/91/1285-2666$03.00/0 Endocrinology Copyright © 1991 by The Endocrine Society
Vol. 128, No. 5 Printed in U.S.A.
Localization of lnterleukln-1 Receptor Messenger RNA in Murlne Hippocampus Emmett T. Cunningham, Jr., Etsuko Wada, Donald B. Carter, Daniel E. Tracey, James F. Battey, and Errol B. De Souza From the Neurobiology Laboratory, National Institute on Drug Abuse, Addiction Research Center (E.T.C. Jr., E.B.D.S.), Baltimore, Maryland 21224; Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health (E.W., J.F.B.), Bethesda, Maryland 20892; and Molecular Biology Research (D.B.C.) and Hypersensitivity Diseases Research (D.E.T.), The Upjohn Company, Kalamazoo, Michigan 49007 ABSTRACT: The cytokine interleukin-1 (IL-1) has numerous actions in brain, including pronounced neuroendocrine effects. Recent radioligand binding studies have identified high-affinity binding sites for 125l-recombinant human IL-1 a in the hippocampus with characteristics similar to those of IL-1 receptors in immune cells. The present study employed insiiU hybridization histochemistry with 35S-labeled anti-sense cRNA probes derived from a full-length murine T-cell IL-1 receptor cDNA to identify cells producing IL-1 receptor mRNA in the murine hippocampus. An intense signal was observed over granule cells in the dentate gyrus. A weak to moderate signal was observed over the pyramidal cell layer of the hilus and CA3 region. Other aspects of the hippocampal formation, including the CA2 and CA1 regions, the subiculum, and the entorhinal area, displayed no signal above background. This distribution of IL-1 receptor mRNA was similar to that of 125I-IL1a binding sites and supports the growing body of evidence implicating IL-1 as a neurotransmitter/neuromodulator in brain. Interleukin-1 (IL-1) has a number of biologic activities, including prominent effects on the central nervous system (1). Perhaps best documented of its effects on the brain are the induction of fever, the alteration of slow wave sleep, and the reduction of appetite (1). In addition, IL-1 has pronounced neuroendocrine effects including inhibition of the hypothalamic-pituitary-gonadal axis (2,3), and the activation of the hypothalamic-pituitaryadrenal axis (see 4). Numerous sources of IL-1 in brain have been postulated, including astrocytes, microglia (5) and nerve fibers (6). To date, however, no studies have provided evidence for any given source as the specific cause of one or more of these central effects. Recent radioligand binding studies have identified high-affinity binding sites for 125l-recombinant human IL-1 a in mouse brain with characteristics stimilar to those of IL-1 receptors in immune cells (7). Autoradiographic localization studies have demonstrated a relatively limited distribution of IL-1 binding sites in the rodent brain, with by far the highest density being found in the dentate gyrus in the hippocampus (7,8). Whether the IL-1 binding sites in brain represent "true" IL-1 receptors is at present unclear, since there are species differences in 125l-recombinant human IL-1 a binding in brain (7). Furthermore, it remains to be demonstrated if the putative IL-1 receptors identified in these studies are produced in the hippocampus, or simply reside on incoming afferent fibers or glial cells. To address these issues, we carried out iflsjlu. hybridization histochemistry to localize IL-1 receptor mRNA in murine hippocampus.
buffer, pH 9.5. The brains were removed and allowed to postfix for 6-8 h in the final perfusate with 10% sucrose added as a cryoprotectant. Three 1-5 series of 20-nm thick coronal sections were cut through the rostro-caudal extent of the hippocampus on a sliding microtome. The first and third series were mounted on lysine-coated slides and processed for sense and anti-sense insitll hybridization as described below. The intervening series was mounted on gelatin-coated slides and stained with thionin for reference. In Situ Hybridization Histochemistrv. A previously characterized murine full-length T-cell IL-1 receptor cDNA was cloned into a pGEM plasmid vector (9). 35S-labeled sense and anti-sense cRNA probes were prepared by transcription with Sp6 and T7 RNA polymerase, respectively (10). The pre-hybridization, hybridization, and autoradiographic localization techniques have been described in detail elsewhere (11). In brief, mounted sections were fixed in the above perfusate for 30 min, after which they were treated with proteinase K, acetylated, and dehydrated. 35s-|abeled cRNA probes (5-10 x 106 cpm/ml) were applied in hybridization buffer, at 55 C overnight. Sections were then treated with RNase A to reduce background, and washed through progressively lower concentrations of saline sodium citrate (SSC) to reduce the salt content and increase the stringency of hybridization. Finally, sections were dehydrated, exposed to either Beta Max (Amersham) or Cronex (DuPont) film for 2-4 days, dipped in Kodak nuclear emulsion NTB3, dried, exposed for 7-21 days, developed, and counter-stained with thionin.
MATERIALS AND METHODS Animals. Seven to eight week old C57BL/6 mice of the Harlan Sprague-Dawley strain (Indianapolis, IN) were used in all experiments. All animals were housed in a light- (12 h on/12 h off) and temperature-controlled environment, with food and water available ad libitum.
RESULTS A total of 9 brains were processed for in situ hybridization histochemistry with anti-sense IL-1 receptor probes. In each case, an intense hybridization signal was observed over granule cells of the dentate gyrus. A weak to moderate signal was also found over the pyramidal cell layer of the hilus and CA3 region. A signal comparable to background was observed over all other aspects of the hippocampal formation, including the CA2 and CA1 regions, the subiculum, and the entorhinal area. Similar patterns were found at all rostro-caudal levels (Figure 1).
Tissue Preparation. All mice were deeply anesthetized with 35% chloral hydrate, and perfused transcardially with 10-15 ml of 0.15 M NaCI, followed immediately by 400 ml of 4% paraformaldehyde in 0.1 M sodium tetraborate
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Figure 1: Darkfield photomicrograph of an emulsion autoradiogram of a coronal section through the hippocampus following i n s i l u hybridization with an antisense probe for IL-1 receptor mRNA (A). An adjacent Nisslstained section is shown for reference (B). Note the dense autoradiographic signal over granule cells in the dentate gyms (DG), and, to a lesser extent, over the pyramidal cell layer of the hilus and CA3 region (arrow). Note also the dense signal over endothelial cells of post-capillary venules (v). Fimbria hippocampus (fi); medial habenular nucleus (Hb).
Figure 2: High-power darkfield photomicrograph of an emulsion autoradiogram of a coronal section through the hippocampus following in situ hybridization with a sense probe for IL-1 receptor mRNA (A). An adjacent Nisslstained section is shown for reference (B). Note that the autoradiographic signal over granule cells in the highly refringent dentate gyms (DG), over the CA3 region, and over endothelial cells of post-capillary venules (not indicated) is, in each case, comparable to background. Medial habenular nucleus (Hb).
An intense hybridization signal was also observed over small to medium sized post-capillary venules in this region, readily distinguished by their size and the absence of a muscular wall (Figure 1). A similar signal was observed over post-capillary venules in other parts of the central nervous system as well (unpublished observation). Previously published Northern blot analyses of mRNA from EL-4 cells demonstrated IL-1 receptor cDNA hybridization to a single 5-kilobase species (9). Signal specificity was further documented in this study by in situ hybridization histochemistry with sense probes, which, in all cases (n=4), generated signal comparable to background (Figure 2).
hippocampal formation showed no signal above background (Figure 1). These results therefore support recent autoradiographic demonstrations of IL-1 binding sites in this region (7,8) and suggest further that IL-1 receptors are normally synthesized and expressed in cells within the hippocampal formation itself. While a glial source for the IL-1 receptor mRNA observed in the hippocampus cannot not be excluded with certainty, the sheer density of signal over the tightly packed granule cell layer, a layer particularly devoid of glial cells (12), would seem to indicate significant neuronal synthesis of IL-1 receptors (Figure 1). Further support for a neuronal localization of IL-1 receptors in the hippocampus comes from recent receptor autoradiographic studies demonstrating a disappearance of IL-1 binding in the dentate gyms in response to quinolinic acid lesion of this brain area (7). It should be noted, however, that hippocampal glial cells outside the dentate gyms have been demonstrated to produce IL-1 in response to perferent path deafferentation (13). Furthermore, both hippocampal neurons and glial cells respond to IL-1 in culture by increasing production of nerve growth factor
DISCUSSION IL-1 receptor mRNA was localized in murine hippocampus with insilu hybridization histochemistry. An intense autoradiographic signal was observed over granule cells in the dentate gyms. A weak to moderate autoradiographic signal was observed over the pyramidal cell layer of the hilus and CA3 region. Other aspects of the
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(NGF) (14,15). Intracerebroventricular injection of IL-1 in rats has also been reported to increase NGF mRNA in the hippocampus (15) . The physiologic role of hippocampal IL-1 receptors is at present unclear. The above mentioned effects of IL-1 on NGF production would seem to implicate the cytokine and its receptor in neuronal survival and/or repair in the hippocampus (14,15). It is tempting to speculate, however, that IL-1 might exert at least a portion of its effects on the hypothalamic-pituitary axes by way of the hippocampus, in a manner similar to the type of feedback regulation hypothesized for circulating glucocorticoids (16). An intense IL-1 receptor mRNA signal was also observed over small to medium sized post-capillary venules in the hippocampal formation (Figure 1), and throughout the central nervous system (unpublished observation). This finding is of particular interest given the well-documented presence of IL-1 receptors on vascular endothelial cells, where it leads to increased adhesion and diapedesis of leukocytes during inflammation (17). It may be, moreover, that circulating IL-1 could gain access to the normally privileged central nervous system by altering the permeability of post-capillary venules. This, however, remains an issue for further experimentation. Address correspondence to Dr. Errol B. De Souza, The Du Pont Merck Pharmaceutical Company, Experimental Station, E400/4352, P. O. Box 80400, Wilmington, DE 19880-0400. Acknowledgments: We thank Dr. Paul E. Sawchenko for helpful technical suggestions, Ms. Melanie Holden, Ms. Jean Gonnella, and Mr. Mark Fleming for their superb photographic assistance and Mrs. Deborah Gorman for help with preparation of the manuscript. E.T. Cunningham, Jr.'s present address is: The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205.
8. 9.
10.
11.
12.
13. 14.
15.
16.
17.
Farrar WL, Kilian PL, Ruff MR, Hill JM, Pert CB 1987 Visualization and characterization of interleukin 1 receptors in brain. J Immunol 139:459-463. Chiou WJ, Bonin PD, Harris PKW, Carter DB, Singh JP 1989 Platelet-derived growth factor induces interleukin-1 receptor gene expression in Balb/c 3T3 fibroblasts. J Biol Chem 264:21442-21445. Wada E, Way J, Lebacq-Verheyden AM, Battey JF 1990 Neuromedin b and gastrin-releasing peptide mRNAs are differentially distributed in the rat nervous system. J Neurosci 10(9):2917-2930. Simmons DM, Arriza JL, Swanson LW 1989 A complete protocol for in situ hybridization of messenger RNAs in brain and other tissues with radio-labeled single-stranded RNA probes. J Histotech 12(3):169-181. Rickmann M, Amaral DG, Cowan WM 1987 Organization of radial glial cells during the development of the rat dentate gyrus. J. Comp. Neurol. 264:449-479. Fagan AM, Gage FH 1990 Cholinergic sprouting in the hippocampus: A proposed role for IL-1. Exp Neurol 110:105-120. Friedman WJ, Larkfors L, Ayer-LeLievre C, Ebendal T, Olson L, Persson H 1990 Regulation of B-nerve growth factor expression by inflammatory mediators in hippocampal cultures. J Neurosci Res 27:374388. Spranger M, Lindholm D, Bandtlow C, Heumann R, Grahn H, Naher-Noe M, Thoenen H 1990 Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur. J. Neurosci. 2:69-76. Jacobson L, Sapolsky L 1991 The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endo Rev (In press). Pober JS, Cotran RS 1990 Cytokines and endothelial cell biology. Physiol Rev 70(2):427451.
REFERENCES 1. 2.
3.
4. 5. 6. 7.
Endo • 1991 Voll28«No5
DinarelloCA1988 Biology of interleukin-1. FASEB J. 2:108-115. Rivier C, Vale W 1989 In the rat, interleukin-1 alpha acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion. Endocrinology 124:2105-2109. Kalra PS, Sahu A, Kalra SP 1990 Interleukin-1 inhibits the ovarian steroid-induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126:2145-2152. Lumpkin MD 1987 The regulation of ACTH by IL-1. Science 238:452-454. Nieto-Sampedro M, Berman MA 1987 Interleukin-1 like activity in rat brain:' Sources, targets, and effect of injury. J Neurosci Res 17:214-219. Breder CD, Dinarello CA, Saper CB 1988 Interleukin-1 immunoreactivity innervation of the human hypothalamus. Science 240:321-324. Takao T, Tracey DE, Mitchell, WM, De Souza EB 1990 Interleukin-1 receptors in mouse brain: Characterization and neuronal localization. Endocrinology 127:3070-3078.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 00:38 For personal use only. No other uses without permission. . All rights reserved.
Vol. 128, No. 5 Printed in U.S.A.
Localization of lnterleukln-1 Receptor Messenger RNA in Murlne Hippocampus Emmett T. Cunningham, Jr., Etsuko Wada, Donald B. Carter, Daniel E. Tracey, James F. Battey, and Errol B. De Souza From the Neurobiology Laboratory, National Institute on Drug Abuse, Addiction Research Center (E.T.C. Jr., E.B.D.S.), Baltimore, Maryland 21224; Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health (E.W., J.F.B.), Bethesda, Maryland 20892; and Molecular Biology Research (D.B.C.) and Hypersensitivity Diseases Research (D.E.T.), The Upjohn Company, Kalamazoo, Michigan 49007 ABSTRACT: The cytokine interleukin-1 (IL-1) has numerous actions in brain, including pronounced neuroendocrine effects. Recent radioligand binding studies have identified high-affinity binding sites for 125l-recombinant human IL-1 a in the hippocampus with characteristics similar to those of IL-1 receptors in immune cells. The present study employed insiiU hybridization histochemistry with 35S-labeled anti-sense cRNA probes derived from a full-length murine T-cell IL-1 receptor cDNA to identify cells producing IL-1 receptor mRNA in the murine hippocampus. An intense signal was observed over granule cells in the dentate gyrus. A weak to moderate signal was observed over the pyramidal cell layer of the hilus and CA3 region. Other aspects of the hippocampal formation, including the CA2 and CA1 regions, the subiculum, and the entorhinal area, displayed no signal above background. This distribution of IL-1 receptor mRNA was similar to that of 125I-IL1a binding sites and supports the growing body of evidence implicating IL-1 as a neurotransmitter/neuromodulator in brain. Interleukin-1 (IL-1) has a number of biologic activities, including prominent effects on the central nervous system (1). Perhaps best documented of its effects on the brain are the induction of fever, the alteration of slow wave sleep, and the reduction of appetite (1). In addition, IL-1 has pronounced neuroendocrine effects including inhibition of the hypothalamic-pituitary-gonadal axis (2,3), and the activation of the hypothalamic-pituitaryadrenal axis (see 4). Numerous sources of IL-1 in brain have been postulated, including astrocytes, microglia (5) and nerve fibers (6). To date, however, no studies have provided evidence for any given source as the specific cause of one or more of these central effects. Recent radioligand binding studies have identified high-affinity binding sites for 125l-recombinant human IL-1 a in mouse brain with characteristics stimilar to those of IL-1 receptors in immune cells (7). Autoradiographic localization studies have demonstrated a relatively limited distribution of IL-1 binding sites in the rodent brain, with by far the highest density being found in the dentate gyrus in the hippocampus (7,8). Whether the IL-1 binding sites in brain represent "true" IL-1 receptors is at present unclear, since there are species differences in 125l-recombinant human IL-1 a binding in brain (7). Furthermore, it remains to be demonstrated if the putative IL-1 receptors identified in these studies are produced in the hippocampus, or simply reside on incoming afferent fibers or glial cells. To address these issues, we carried out iflsjlu. hybridization histochemistry to localize IL-1 receptor mRNA in murine hippocampus.
buffer, pH 9.5. The brains were removed and allowed to postfix for 6-8 h in the final perfusate with 10% sucrose added as a cryoprotectant. Three 1-5 series of 20-nm thick coronal sections were cut through the rostro-caudal extent of the hippocampus on a sliding microtome. The first and third series were mounted on lysine-coated slides and processed for sense and anti-sense insitll hybridization as described below. The intervening series was mounted on gelatin-coated slides and stained with thionin for reference. In Situ Hybridization Histochemistrv. A previously characterized murine full-length T-cell IL-1 receptor cDNA was cloned into a pGEM plasmid vector (9). 35S-labeled sense and anti-sense cRNA probes were prepared by transcription with Sp6 and T7 RNA polymerase, respectively (10). The pre-hybridization, hybridization, and autoradiographic localization techniques have been described in detail elsewhere (11). In brief, mounted sections were fixed in the above perfusate for 30 min, after which they were treated with proteinase K, acetylated, and dehydrated. 35s-|abeled cRNA probes (5-10 x 106 cpm/ml) were applied in hybridization buffer, at 55 C overnight. Sections were then treated with RNase A to reduce background, and washed through progressively lower concentrations of saline sodium citrate (SSC) to reduce the salt content and increase the stringency of hybridization. Finally, sections were dehydrated, exposed to either Beta Max (Amersham) or Cronex (DuPont) film for 2-4 days, dipped in Kodak nuclear emulsion NTB3, dried, exposed for 7-21 days, developed, and counter-stained with thionin.
MATERIALS AND METHODS Animals. Seven to eight week old C57BL/6 mice of the Harlan Sprague-Dawley strain (Indianapolis, IN) were used in all experiments. All animals were housed in a light- (12 h on/12 h off) and temperature-controlled environment, with food and water available ad libitum.
RESULTS A total of 9 brains were processed for in situ hybridization histochemistry with anti-sense IL-1 receptor probes. In each case, an intense hybridization signal was observed over granule cells of the dentate gyrus. A weak to moderate signal was also found over the pyramidal cell layer of the hilus and CA3 region. A signal comparable to background was observed over all other aspects of the hippocampal formation, including the CA2 and CA1 regions, the subiculum, and the entorhinal area. Similar patterns were found at all rostro-caudal levels (Figure 1).
Tissue Preparation. All mice were deeply anesthetized with 35% chloral hydrate, and perfused transcardially with 10-15 ml of 0.15 M NaCI, followed immediately by 400 ml of 4% paraformaldehyde in 0.1 M sodium tetraborate
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2667
Figure 1: Darkfield photomicrograph of an emulsion autoradiogram of a coronal section through the hippocampus following i n s i l u hybridization with an antisense probe for IL-1 receptor mRNA (A). An adjacent Nisslstained section is shown for reference (B). Note the dense autoradiographic signal over granule cells in the dentate gyms (DG), and, to a lesser extent, over the pyramidal cell layer of the hilus and CA3 region (arrow). Note also the dense signal over endothelial cells of post-capillary venules (v). Fimbria hippocampus (fi); medial habenular nucleus (Hb).
Figure 2: High-power darkfield photomicrograph of an emulsion autoradiogram of a coronal section through the hippocampus following in situ hybridization with a sense probe for IL-1 receptor mRNA (A). An adjacent Nisslstained section is shown for reference (B). Note that the autoradiographic signal over granule cells in the highly refringent dentate gyms (DG), over the CA3 region, and over endothelial cells of post-capillary venules (not indicated) is, in each case, comparable to background. Medial habenular nucleus (Hb).
An intense hybridization signal was also observed over small to medium sized post-capillary venules in this region, readily distinguished by their size and the absence of a muscular wall (Figure 1). A similar signal was observed over post-capillary venules in other parts of the central nervous system as well (unpublished observation). Previously published Northern blot analyses of mRNA from EL-4 cells demonstrated IL-1 receptor cDNA hybridization to a single 5-kilobase species (9). Signal specificity was further documented in this study by in situ hybridization histochemistry with sense probes, which, in all cases (n=4), generated signal comparable to background (Figure 2).
hippocampal formation showed no signal above background (Figure 1). These results therefore support recent autoradiographic demonstrations of IL-1 binding sites in this region (7,8) and suggest further that IL-1 receptors are normally synthesized and expressed in cells within the hippocampal formation itself. While a glial source for the IL-1 receptor mRNA observed in the hippocampus cannot not be excluded with certainty, the sheer density of signal over the tightly packed granule cell layer, a layer particularly devoid of glial cells (12), would seem to indicate significant neuronal synthesis of IL-1 receptors (Figure 1). Further support for a neuronal localization of IL-1 receptors in the hippocampus comes from recent receptor autoradiographic studies demonstrating a disappearance of IL-1 binding in the dentate gyms in response to quinolinic acid lesion of this brain area (7). It should be noted, however, that hippocampal glial cells outside the dentate gyms have been demonstrated to produce IL-1 in response to perferent path deafferentation (13). Furthermore, both hippocampal neurons and glial cells respond to IL-1 in culture by increasing production of nerve growth factor
DISCUSSION IL-1 receptor mRNA was localized in murine hippocampus with insilu hybridization histochemistry. An intense autoradiographic signal was observed over granule cells in the dentate gyms. A weak to moderate autoradiographic signal was observed over the pyramidal cell layer of the hilus and CA3 region. Other aspects of the
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(NGF) (14,15). Intracerebroventricular injection of IL-1 in rats has also been reported to increase NGF mRNA in the hippocampus (15) . The physiologic role of hippocampal IL-1 receptors is at present unclear. The above mentioned effects of IL-1 on NGF production would seem to implicate the cytokine and its receptor in neuronal survival and/or repair in the hippocampus (14,15). It is tempting to speculate, however, that IL-1 might exert at least a portion of its effects on the hypothalamic-pituitary axes by way of the hippocampus, in a manner similar to the type of feedback regulation hypothesized for circulating glucocorticoids (16). An intense IL-1 receptor mRNA signal was also observed over small to medium sized post-capillary venules in the hippocampal formation (Figure 1), and throughout the central nervous system (unpublished observation). This finding is of particular interest given the well-documented presence of IL-1 receptors on vascular endothelial cells, where it leads to increased adhesion and diapedesis of leukocytes during inflammation (17). It may be, moreover, that circulating IL-1 could gain access to the normally privileged central nervous system by altering the permeability of post-capillary venules. This, however, remains an issue for further experimentation. Address correspondence to Dr. Errol B. De Souza, The Du Pont Merck Pharmaceutical Company, Experimental Station, E400/4352, P. O. Box 80400, Wilmington, DE 19880-0400. Acknowledgments: We thank Dr. Paul E. Sawchenko for helpful technical suggestions, Ms. Melanie Holden, Ms. Jean Gonnella, and Mr. Mark Fleming for their superb photographic assistance and Mrs. Deborah Gorman for help with preparation of the manuscript. E.T. Cunningham, Jr.'s present address is: The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205.
8. 9.
10.
11.
12.
13. 14.
15.
16.
17.
Farrar WL, Kilian PL, Ruff MR, Hill JM, Pert CB 1987 Visualization and characterization of interleukin 1 receptors in brain. J Immunol 139:459-463. Chiou WJ, Bonin PD, Harris PKW, Carter DB, Singh JP 1989 Platelet-derived growth factor induces interleukin-1 receptor gene expression in Balb/c 3T3 fibroblasts. J Biol Chem 264:21442-21445. Wada E, Way J, Lebacq-Verheyden AM, Battey JF 1990 Neuromedin b and gastrin-releasing peptide mRNAs are differentially distributed in the rat nervous system. J Neurosci 10(9):2917-2930. Simmons DM, Arriza JL, Swanson LW 1989 A complete protocol for in situ hybridization of messenger RNAs in brain and other tissues with radio-labeled single-stranded RNA probes. J Histotech 12(3):169-181. Rickmann M, Amaral DG, Cowan WM 1987 Organization of radial glial cells during the development of the rat dentate gyrus. J. Comp. Neurol. 264:449-479. Fagan AM, Gage FH 1990 Cholinergic sprouting in the hippocampus: A proposed role for IL-1. Exp Neurol 110:105-120. Friedman WJ, Larkfors L, Ayer-LeLievre C, Ebendal T, Olson L, Persson H 1990 Regulation of B-nerve growth factor expression by inflammatory mediators in hippocampal cultures. J Neurosci Res 27:374388. Spranger M, Lindholm D, Bandtlow C, Heumann R, Grahn H, Naher-Noe M, Thoenen H 1990 Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur. J. Neurosci. 2:69-76. Jacobson L, Sapolsky L 1991 The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endo Rev (In press). Pober JS, Cotran RS 1990 Cytokines and endothelial cell biology. Physiol Rev 70(2):427451.
REFERENCES 1. 2.
3.
4. 5. 6. 7.
Endo • 1991 Voll28«No5
DinarelloCA1988 Biology of interleukin-1. FASEB J. 2:108-115. Rivier C, Vale W 1989 In the rat, interleukin-1 alpha acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion. Endocrinology 124:2105-2109. Kalra PS, Sahu A, Kalra SP 1990 Interleukin-1 inhibits the ovarian steroid-induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126:2145-2152. Lumpkin MD 1987 The regulation of ACTH by IL-1. Science 238:452-454. Nieto-Sampedro M, Berman MA 1987 Interleukin-1 like activity in rat brain:' Sources, targets, and effect of injury. J Neurosci Res 17:214-219. Breder CD, Dinarello CA, Saper CB 1988 Interleukin-1 immunoreactivity innervation of the human hypothalamus. Science 240:321-324. Takao T, Tracey DE, Mitchell, WM, De Souza EB 1990 Interleukin-1 receptors in mouse brain: Characterization and neuronal localization. Endocrinology 127:3070-3078.
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