Skip to main content
PMC home page
The Yale Journal of Biology and Medicine logoLink to The Yale Journal of Biology and Medicine
. 1990 Mar-Apr;63(2):147–156.

Hypothalamic neuronal responses to cytokines.

M Shibata 1
PMCID: PMC2589303  PMID: 2205055

Abstract

Fever has been extensively studied in the past few decades. The hypothesis that hypothalamic thermosensitive neurons play a major role in both normal thermoregulation and in fever production and lysis has particularly helped to advance our understanding of the neuronal mechanisms underlying the response to pyrogens. Furthermore, new data in the study of host defense responses induced by pyrogenic cytokines such as interleukin 1, interferon alpha 2, tumor necrosis factor alpha, and interleukin 6 have demonstrated that those factors have multiple, yet coordinated, regulatory activities in the central nervous system, so that our understanding of the role of the brain in the activity of these agents requires a new perspective and dimension. Thus, recent evidence from our laboratory indicates that blood-borne cytokines may be detected in the organum vasculosum laminae terminalis and transduced there into neuronal signals. Such signals may then affect distinct, but partially overlapping, sets of neuronal systems in the preoptic area of the anterior hypothalamus, mediating directly and/or indirectly the array of various host defense responses characteristic of infection that are thought to be induced by blood-borne cytokines.

Full text

PDF
153

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bagust J., Kerkut G. A. Some effects of magnesium ions upon conduction and synaptic activity in the isolated spinal cord of the mouse. Brain Res. 1979 Nov 16;177(2):410–413. doi: 10.1016/0006-8993(79)90796-0. [DOI] [PubMed] [Google Scholar]
  2. Baldino F., Jr, Geller H. M. Electrophysiological analysis of neuronal thermosensitivity in rat preoptic and hypothalamic tissue cultures. J Physiol. 1982 Jun;327:173–184. doi: 10.1113/jphysiol.1982.sp014226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barker J. L., Carpenter D. O. Thermosensitivity of neurons in the sensorimotor cortex of the cat. Science. 1970 Aug 7;169(3945):597–598. doi: 10.1126/science.169.3945.597. [DOI] [PubMed] [Google Scholar]
  4. Bernheim H. A., Gilbert T. M., Stitt J. T. Prostaglandin E levels in third ventricular cerebrospinal fluid of rabbits during fever and changes in body temperature. J Physiol. 1980 Apr;301:69–78. doi: 10.1113/jphysiol.1980.sp013189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blatteis C. M., Bealer S. L., Hunter W. S., Llanos-Q J., Ahokas R. A., Mashburn T. A., Jr Suppression of fever after lesions of the anteroventral third ventricle in guinea pigs. Brain Res Bull. 1983 Nov;11(5):519–526. doi: 10.1016/0361-9230(83)90124-7. [DOI] [PubMed] [Google Scholar]
  6. Blatteis C. M., Hales J. R., McKinley M. J., Fawcett A. A. Role of the anteroventral third ventricle region in fever in sheep. Can J Physiol Pharmacol. 1987 Jun;65(6):1255–1260. doi: 10.1139/y87-200. [DOI] [PubMed] [Google Scholar]
  7. Blatteis C. M., Hunter W. S., Llanos J., Ahokas R. A., Mashburn T. A., Jr Activation of acute-phase responses by intrapreoptic injections of endogenous pyrogen in guinea pigs. Brain Res Bull. 1984 Jun;12(6):689–695. doi: 10.1016/0361-9230(84)90149-7. [DOI] [PubMed] [Google Scholar]
  8. Blatteis C. M. Neural mechanisms in the pyrogenic and acute-phase responses to interleukin-1. Int J Neurosci. 1988 Jan;38(1-2):223–232. doi: 10.3109/00207458809000500. [DOI] [PubMed] [Google Scholar]
  9. Bosler O. Radioautographic identification of serotonin axon terminals in the rat organum vasculosum laminae terminalis. Brain Res. 1978 Jul 7;150(1):177–181. doi: 10.1016/0006-8993(78)90662-5. [DOI] [PubMed] [Google Scholar]
  10. Boulant J. A., Dean J. B. Temperature receptors in the central nervous system. Annu Rev Physiol. 1986;48:639–654. doi: 10.1146/annurev.ph.48.030186.003231. [DOI] [PubMed] [Google Scholar]
  11. Boulant J. A., Hardy J. D. The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones. J Physiol. 1974 Aug;240(3):639–660. doi: 10.1113/jphysiol.1974.sp010627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Boulant J. A., Silva N. L. Interactions of reproductive steroids, osmotic pressure, and glucose on thermosensitive neurons in preoptic tissue slices. Can J Physiol Pharmacol. 1987 Jun;65(6):1267–1273. doi: 10.1139/y87-202. [DOI] [PubMed] [Google Scholar]
  13. Boulant J. A., Silva N. L. Neuronal sensitivities in preoptic tissue slices: interactions among homeostatic systems. Brain Res Bull. 1988 Jun;20(6):871–878. doi: 10.1016/0361-9230(88)90104-9. [DOI] [PubMed] [Google Scholar]
  14. Coceani F., Lees J., Bishai I. Further evidence implicating prostaglandin E2 in the genesis of pyrogen fever. Am J Physiol. 1988 Mar;254(3 Pt 2):R463–R469. doi: 10.1152/ajpregu.1988.254.3.R463. [DOI] [PubMed] [Google Scholar]
  15. Coceani F., Lees J., Dinarello C. A. Occurrence of interleukin-1 in cerebrospinal fluid of the conscious cat. Brain Res. 1988 Apr 19;446(2):245–250. doi: 10.1016/0006-8993(88)90883-9. [DOI] [PubMed] [Google Scholar]
  16. Crawshaw L. I., Stitt J. T. Behavioural and autonomic induction of prostaglandin E-1 fever in squirrel monkeys. J Physiol. 1975 Jan;244(1):197–206. doi: 10.1113/jphysiol.1975.sp010791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cunningham D. J., Stolwijk J. A., Murakami N., Hardy J. D. Responses of neurons in the preoptic area to temperature, serotonin, and epinephrine. Am J Physiol. 1967 Dec;213(6):1570–1581. doi: 10.1152/ajplegacy.1967.213.6.1570. [DOI] [PubMed] [Google Scholar]
  18. Dascombe M. J., Milton A. S. Study on the possible entry of bacterial endotoxin and prostaglandin E2 into the central nervous system from the blood. Br J Pharmacol. 1979 Aug;66(4):565–572. doi: 10.1111/j.1476-5381.1979.tb13695.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dean J. B., Boulant J. A. In vitro localization of thermosensitive neurons in the rat diencephalon. Am J Physiol. 1989 Jul;257(1 Pt 2):R57–R64. doi: 10.1152/ajpregu.1989.257.1.R57. [DOI] [PubMed] [Google Scholar]
  20. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  21. Dinarello C. A. Interleukin-1. Rev Infect Dis. 1984 Jan-Feb;6(1):51–95. doi: 10.1093/clinids/6.1.51. [DOI] [PubMed] [Google Scholar]
  22. Eisenman J. S., Jackson D. C. Thermal response patterns of septal and preoptic neurons in cats. Exp Neurol. 1967 Sep;19(1):33–45. doi: 10.1016/0014-4886(67)90005-2. [DOI] [PubMed] [Google Scholar]
  23. Eisenman J. S. Pyrogen-induced changes in the thermosensitivity of septal and preoptic neurons. Am J Physiol. 1969 Feb;216(2):330–334. doi: 10.1152/ajplegacy.1969.216.2.330. [DOI] [PubMed] [Google Scholar]
  24. FREEMAN W. J., DAVIS D. D. Effects on cats of conductive hypothalamic cooling. Am J Physiol. 1959 Jul;197(1):145–148. doi: 10.1152/ajplegacy.1959.197.1.145. [DOI] [PubMed] [Google Scholar]
  25. Feldberg W., Gupta K. P., Milton A. S., Wendlandt S. Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. J Physiol. 1973 Oct;234(2):279–303. doi: 10.1113/jphysiol.1973.sp010346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Feldberg W., Gupta K. P. Pyrogen fever and prostaglandin-like activity in cerebrospinal fluid. J Physiol. 1973 Jan;228(1):41–53. doi: 10.1113/jphysiol.1973.sp010071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Feldberg W., Saxena P. N. Fever produced by prostaglandin E1. J Physiol. 1971 Sep;217(3):547–556. doi: 10.1113/jphysiol.1971.sp009585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Feldberg W., Saxena P. N. Further studies on prostaglandin E 1 fever in cats. J Physiol. 1971 Dec;219(3):739–745. doi: 10.1113/jphysiol.1971.sp009686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Flower R. J., Vane J. R. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol). Nature. 1972 Dec 15;240(5381):410–411. doi: 10.1038/240410a0. [DOI] [PubMed] [Google Scholar]
  30. Gilman S. C., Chang J., Zeigler P. R., Uhl J., Mochan E. Interleukin-1 activates phospholipase A2 in human synovial cells. Arthritis Rheum. 1988 Jan;31(1):126–130. doi: 10.1002/art.1780310118. [DOI] [PubMed] [Google Scholar]
  31. Giulian D., Baker T. J., Shih L. C., Lachman L. B. Interleukin 1 of the central nervous system is produced by ameboid microglia. J Exp Med. 1986 Aug 1;164(2):594–604. doi: 10.1084/jem.164.2.594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. HAMMEL H. T., HARDY J. D., FUSCO M. M. Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am J Physiol. 1960 Mar;198:481–486. doi: 10.1152/ajplegacy.1960.198.3.481. [DOI] [PubMed] [Google Scholar]
  33. HARDY J. D., HELLON R. F., SUTHERLAND K. TEMPERATURE-SENSITIVE NEURONES IN THE DOG'S HYPOTHALAMUS. J Physiol. 1964 Dec;175:242–253. doi: 10.1113/jphysiol.1964.sp007515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hellon R. F. The stimulation of hypothalamic neurones by changes in ambient temperature. Pflugers Arch. 1970;321(1):56–66. doi: 10.1007/BF00594122. [DOI] [PubMed] [Google Scholar]
  35. Hori T., Nakashima T., Hori N., Kiyohara T. Thermo-sensitive neurons in hypothalamic tissue slices in vitro. Brain Res. 1980 Mar 17;186(1):203–207. doi: 10.1016/0006-8993(80)90266-8. [DOI] [PubMed] [Google Scholar]
  36. Hori T., Nakashima T., Kiyohara T., Shibata M., Hori N. Effect of calcium removal on thermosensitivity of preoptic neurons in hypothalamic slices. Neurosci Lett. 1980 Nov;20(2):171–175. doi: 10.1016/0304-3940(80)90141-x. [DOI] [PubMed] [Google Scholar]
  37. Hori T., Shibata M., Nakashima T., Yamasaki M., Asami A., Asami T., Koga H. Effects of interleukin-1 and arachidonate on the preoptic and anterior hypothalamic neurons. Brain Res Bull. 1988 Jan;20(1):75–82. doi: 10.1016/0361-9230(88)90010-x. [DOI] [PubMed] [Google Scholar]
  38. Hunter W. S., Blatteis C. M., Llanos-Q J., Mashburn T. A., Jr, Ahokas R. A. Thermal stimulation of the hypothalamus does not evoke the acute-phase reaction. Brain Res Bull. 1987 Jul;19(1):69–74. doi: 10.1016/0361-9230(87)90167-5. [DOI] [PubMed] [Google Scholar]
  39. Inenaga K., Osaka T., Yamashita H. Thermosensitivity of neurons in the paraventricular nucleus of the rat slice preparation. Brain Res. 1987 Oct 20;424(1):126–132. doi: 10.1016/0006-8993(87)91201-7. [DOI] [PubMed] [Google Scholar]
  40. Jell R. M., Sweatman P. Prostaglandin-sensitive neurones in cat hypothalamus: relation to thermoregulation and to biogenic amines. Can J Physiol Pharmacol. 1977 Jun;55(3):560–567. doi: 10.1139/y77-078. [DOI] [PubMed] [Google Scholar]
  41. Kelso S. R., Boulant J. A. Effect of synaptic blockade on thermosensitive neurons in hypothalamic tissue slices. Am J Physiol. 1982 Nov;243(5):R480–R490. doi: 10.1152/ajpregu.1982.243.5.R480. [DOI] [PubMed] [Google Scholar]
  42. Kelso S. R., Perlmutter M. N., Boulant J. A. Thermosensitive single-unit activity of in vitro hypothalamic slices. Am J Physiol. 1982 Jan;242(1):R77–R84. doi: 10.1152/ajpregu.1982.242.1.R77. [DOI] [PubMed] [Google Scholar]
  43. Krueger J. M., Walter J., Dinarello C. A., Wolff S. M., Chedid L. Sleep-promoting effects of endogenous pyrogen (interleukin-1). Am J Physiol. 1984 Jun;246(6 Pt 2):R994–R999. doi: 10.1152/ajpregu.1984.246.6.R994. [DOI] [PubMed] [Google Scholar]
  44. Lipton J. M., Welch J. P., Clark W. G. Changes in body temperature produced by injecting prostaglandin E1, EGTA and bacterial endotoxins into the PO-AH region and the medulla oblongata of the rat. Experientia. 1973;29(7):806–808. doi: 10.1007/BF01946298. [DOI] [PubMed] [Google Scholar]
  45. Milton A. S., Wendlandt S. Effects on body temperature of prostaglandins of the A, E and F series on injection into the third ventricle of unanaesthetized cats and rabbits. J Physiol. 1971 Oct;218(2):325–336. doi: 10.1113/jphysiol.1971.sp009620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. NAKAYAMA T., EISENMAN J. S., HARDY J. D. Single unit activity of anterior hypothalamus during local heating. Science. 1961 Aug 25;134(3478):560–561. doi: 10.1126/science.134.3478.560. [DOI] [PubMed] [Google Scholar]
  47. Nakashima T., Hori T., Kuriyama K., Matsuda T. Effects of interferon-alpha on the activity of preoptic thermosensitive neurons in tissue slices. Brain Res. 1988 Jun 28;454(1-2):361–367. doi: 10.1016/0006-8993(88)90838-4. [DOI] [PubMed] [Google Scholar]
  48. Nakayama T., Ishikawa Y., Tsurutani T. Projection of scrotal thermal afferents to the preoptic and hypothalamic neurons in rats. Pflugers Arch. 1979 May 15;380(1):59–64. doi: 10.1007/BF00582613. [DOI] [PubMed] [Google Scholar]
  49. Nakayama T. Neuronal activities related to thermoregulation. Yale J Biol Med. 1986 Mar-Apr;59(2):189–195. [PMC free article] [PubMed] [Google Scholar]
  50. Nelson D. O., Prosser C. L. Intracellular recordings from thermosensitive preoptic neurons. Science. 1981 Aug 14;213(4509):787–789. doi: 10.1126/science.7256280. [DOI] [PubMed] [Google Scholar]
  51. Pfeilschifter J., Pignat W., Vosbeck K., Märki F. Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun. 1989 Mar 15;159(2):385–394. doi: 10.1016/0006-291x(89)90003-x. [DOI] [PubMed] [Google Scholar]
  52. ROWLEY D., HOWARD J. G., JENKIN C. R. The fate of 32P-labelled bacterial lipopolysaccharide in laboratory animals. Lancet. 1956 Apr 7;270(6919):366–367. doi: 10.1016/s0140-6736(56)90110-6. [DOI] [PubMed] [Google Scholar]
  53. Richards C. D., Sercombe R. Calcium, magnesium and the electrical activity of guinea-pig olfactory coex in vitro. J Physiol. 1970 Dec;211(3):571–584. doi: 10.1113/jphysiol.1970.sp009294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. STROM G. Effect of hypothalamic cooling on cutaneous blood flow in the unanesthetized dog. Acta Physiol Scand. 1950 Nov;21(2-3):271–277. doi: 10.1111/j.1748-1716.1950.tb00735.x. [DOI] [PubMed] [Google Scholar]
  55. Schoener E. P., Wang S. C. Effects of locally administered prostaglandin E1 on anterior hypothalamic neurons. Brain Res. 1976 Nov 19;117(1):157–162. doi: 10.1016/0006-8993(76)90567-9. [DOI] [PubMed] [Google Scholar]
  56. Schoener E. P., Wang S. C. Leukocytic pyrogen and sodium acetylsalicylate on hypothalamic neurons in the cat. Am J Physiol. 1975 Jul;229(1):185–190. doi: 10.1152/ajplegacy.1975.229.1.185. [DOI] [PubMed] [Google Scholar]
  57. Scott I. M., Fertel R. H., Boulant J. A. Leukocytic pyrogen effects on prostaglandins in hypothalamic tissue slices. Am J Physiol. 1987 Jul;253(1 Pt 2):R71–R76. doi: 10.1152/ajpregu.1987.253.1.R71. [DOI] [PubMed] [Google Scholar]
  58. Silva N. L., Boulant J. A. Effects of osmotic pressure, glucose, and temperature on neurons in preoptic tissue slices. Am J Physiol. 1984 Aug;247(2 Pt 2):R335–R345. doi: 10.1152/ajpregu.1984.247.2.R335. [DOI] [PubMed] [Google Scholar]
  59. Silva N. L., Boulant J. A. Effects of testosterone, estradiol, and temperature on neurons in preoptic tissue slices. Am J Physiol. 1986 Apr;250(4 Pt 2):R625–R632. doi: 10.1152/ajpregu.1986.250.4.R625. [DOI] [PubMed] [Google Scholar]
  60. Sirko S., Bishai I., Coceani F. Prostaglandin formation in the hypothalamus in vivo: effect of pyrogens. Am J Physiol. 1989 Mar;256(3 Pt 2):R616–R624. doi: 10.1152/ajpregu.1989.256.3.R616. [DOI] [PubMed] [Google Scholar]
  61. Stitt J. T. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol. 1985 Nov;368:501–511. doi: 10.1113/jphysiol.1985.sp015872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Stitt J. T., Hardy J. D. Microelectrophoresis of PGE1 onto single units in the rabbit hypothalamus. Am J Physiol. 1975 Jul;229(1):240–245. doi: 10.1152/ajplegacy.1975.229.1.240. [DOI] [PubMed] [Google Scholar]
  63. Stitt J. T. Prosaglandin E1 fever induced in rabbits. J Physiol. 1973 Jul;232(1):163–179. doi: 10.1113/jphysiol.1973.sp010262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Stitt J. T. Prostaglandin E as the neural mediator of the febrile response. Yale J Biol Med. 1986 Mar-Apr;59(2):137–149. [PMC free article] [PubMed] [Google Scholar]
  65. Stitt J. T., Shimada S. G. Enhancement of the febrile responses of rats to endogenous pyrogen occurs within the OVLT region. J Appl Physiol (1985) 1989 Nov;67(5):1740–1746. doi: 10.1152/jappl.1989.67.5.1740. [DOI] [PubMed] [Google Scholar]
  66. Stitt J. T., Shimada S. G. Immunoadjuvants enhance the febrile responses of rats to endogenous pyrogen. J Appl Physiol (1985) 1989 Nov;67(5):1734–1739. doi: 10.1152/jappl.1989.67.5.1734. [DOI] [PubMed] [Google Scholar]
  67. Williams J. W., Rudy T. A., Yaksh T. L., Viswanathan C. T. An extensive exploration of the rat brain for sites mediating prostaglandin-induced hyperthermia. Brain Res. 1977 Jan 21;120(2):251–262. doi: 10.1016/0006-8993(77)90904-0. [DOI] [PubMed] [Google Scholar]
  68. Wit A., Wang S. C. Temperature-sensitive neurons in preoptic-anterior hypothalamic region: actions of pyrogen and acetylsalicylate. Am J Physiol. 1968 Nov;215(5):1160–1169. doi: 10.1152/ajplegacy.1968.215.5.1160. [DOI] [PubMed] [Google Scholar]

Articles from The Yale Journal of Biology and Medicine are provided here courtesy of Yale Journal of Biology and Medicine

RESOURCES