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. 2002 Jan;6(4):218–228. doi: 10.1007/BF02897973

Stress- and aging-associated modulation of macrophage functions

Takako Kizaki 1,✉, Kenji Suzuki 1, Tomomi Ookawara 2, Tetsuya Izawa 3, Daizoh Saitoh 4, Shuji Oh-Ishi 5, Keiichiro Suzuki 2, Shukoh Haga 6, Hideki Ohno 1
PMCID: PMC2723472  PMID: 21432338

Abstract

Effects of environmental (cold) stress and aging on cells in monocyte/macrophage lineage were investigated. We demonstrated that immune suppressive states seen in acute cold-stressed mice (8–10 weeks of age) is attributable to FcγRIIbright suppressor macrophages. Serum corticosterone levels were markedly increased in acute cold-stressed mice. In addition, expression of glucocorticoids (GC) receptor mRNA was observed in FcγRIIbright cells from these mice. The increase of FcγRIIbright cells in peritoneal exudate cells caused by acute cold stress was inhibited by adrenalectomy or administration of a saturating amount of the GC antagonist RU 38486 (mifepristone). On the contrary, administration of the GC agonist, dexamethasone, markedly increased the proportion of FcγRIIbright cells in peritoneal exudate cells of control mice. These results suggest that the generation of FcγRIIbright suppressor cells of monocyte/macrophage lineage by acute cold stress was mediated by action of GC through the GC receptor. We likewise found that the proportion of FcγRIIbright suppressor macrophages is increased in aged mice (22–24 months of age). Meanwhile, activated macrophages which function as antigen presenting cells were decreased in aged rats. Both the basal corticosterone concentrations in serum and the expression of mRNA for GC receptor in peritoneal macrophages increased significantly in aged animals, suggesting that these populational and functional changes of macrophages in aged animals were mediated, in part, by the increased basal levels of GC. This is probably being responsible for immunosenescence.

Key words: macrophage, stress, aging, glucocorticoid, immunosuppression

References

  • 1).Mason D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol. Today 1991; 12: 57–60. [DOI] [PubMed]
  • 2).Irwin M. Stress-induced immune suppression: Role of the autonomic nervous system. Ann. N.Y. Acad. Sci. 1993; 697: 203–218. [DOI] [PubMed]
  • 3).Ben-Nathan D, Lustig S, Feuerstein G. The influence of cold or isolation stress on neuroinvasiveness and virulence of an attenuated variant of West Nile virus. Arch. Virol. 1989; 109: 1–10. [DOI] [PubMed]
  • 4).Hueber T, Evans WS, Hardy M. Hymenolepis diminuta: The effect of cold temperature exposure on infections in mice. Exp. Parasitol. 1990; 70: 398–403. [DOI] [PubMed]
  • 5).St. Rose JEM, Sabiston BH. Effect of cold exposure on the immunologic response of rabbits to human serum albumin. J. Immunol. 1971; 107: 339–343. [PubMed]
  • 6).Sabiston BH, St. Rose JEM. Effect of cold exposure on the metabolism of immunoglobulins in rabbits. J. Immunol. 1976; 116: 106–111. [PubMed]
  • 7).Holub M, Vetvicka V, Houstek J, Janiková D, Rychter Z, Vrána A, Kazdová L. In: Immune-Deficient Animals in Experimental Medicine. 6th Int. Workshop on Immune-Deficient Animals, Beijing, Wu B-q, Zheng J editors. Influence of ambient temperature on nude mouse metabolic and immune status. Basel, Karger. 1989: 68.
  • 8).Unnanue ER, Allen PM. The basis for the immunoregulatory role of macrophages and other cells. Science 1987; 236: 551–557. [DOI] [PubMed]
  • 9).Johnston RB Jr. Monocytes and macrophages. N. Engl. J. Med. 318: 747–752. [DOI] [PubMed]
  • 10).Chang TW. 1985 Regulation of immune response by antibodies: the importance of antibody and monocyte Fc receptor interaction in T-cell activation. Immunol. Today 1988; 6: 245–249. [DOI] [PubMed]
  • 11).Unkeless JC. Function and heterogeneity of human Fc receptors for immunoglobulin G. J. Clin. Invest. 1989; 83: 355–361. [DOI] [PMC free article] [PubMed]
  • 12).Huizinga TWJ, Kemenade FV, Koenderman L, Dolman KM, Borne AEG, Tetteroo PAT, Roos D. The 40-kDa Fcγ receptor (FcRIII) on human neutrophils is essential for the IgG-induced respiratory burst and IgG-induced phagocytosis. J. Immunol. 1989; 142: 2365–2376. [PubMed]
  • 13).MacIntyre EA, Roberts PJ, Jones M, Van Der Schoot CE, Favalaro EJ, Tidman N, Linch DC. Activation of human monocytes occurs on cross-linking monocytic antigens to a Fc receptor. J. Immunol. 1989; 142: 2377–2383. [PubMed]
  • 14).Fanger MW, Shen L, Graziano RF, Guyre PM. Cytotoxicity mediated by human Fc receptors for IgG. Immunol. Today. 1989; 10: 92–99. [DOI] [PubMed]
  • 15).Rouzer CA, Scott WA, Kempe J, Cohn ZA. Prostaglandin synthesis by macrophages requires a specific receptor ligand interaction. Proc. Natl. Acad. Sci. USA 1980; 77: 4279–4282. [DOI] [PMC free article] [PubMed]
  • 16).Yamamoto K, Johnston RB. Dissociation of phagocytosis from stimulation of the oxidative metabolic burst in macrophages. J. Exp. Med. 1984; 159: 405–416. [DOI] [PMC free article] [PubMed]
  • 17).Kishimoto TK, Larson RS, Corbi AL, Dustin ML, Staunton DE, Springer TA. The leukocyte integrins. Adv. Immunol. 1989; 46: 149–182. [DOI] [PubMed]
  • 18).Allison AC. Mechanisms by which activated macrophages inhibit lymphocyte responses. Immunol. Rev. 1978; 40: 1–26. [DOI] [PubMed]
  • 19).Metzger Z, Hoffeld JT, Oppenheim JJ. MACrophage-mediated suppression. I. Evidence for participation of both hydrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation. J. Immunol. 1980; 124: 983–988. [PubMed]
  • 20).Blalock JE. A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol. Rev. 1989; 69: 1–32. [DOI] [PubMed]
  • 21).De Souza EB. Corticotropin-releasing factor and interleukin-1 receptors in the brain-endocrine-immune axis. Ann. N.Y. Acad. Sci. 1993; 697: 9–27. [DOI] [PubMed]
  • 22).Jefferies WM. Cortisol and immunity. Medical Hypotheses 1991; 34: 198–208. [DOI] [PubMed]
  • 23).Lázár G, Lázár G Jr, Husztik E, Duda E, Agarwal MK. The influence of antiglucocorticoids on stress and shock. Ann. N.Y. Acad. Sci. 1993; 761: 276–295. [DOI] [PubMed]
  • 24).Lipschitz DA, Golkdstein S, Reis R, Weksler ME, Gressler R, Weilan BA. Cancer in the elderly: basic science and clinical aspect. Ann. Intern. Med. 1985; 102: 218–228. [DOI] [PubMed]
  • 25).Makinodam T, James SJ, Inamizu T, Chang MP. Immunologic basis for susceptibility to infection in the aged. Gerontology 1984; 30: 279–289. [DOI] [PubMed]
  • 26).Thoman ML, Weigle WO. The cellular and subcellular bases of immunosenescence. Adv. Immunol. 1989; 46: 221–261. [DOI] [PubMed]
  • 27).Miller RA. Aging and immune function. Int. Rev. Cytol. 1991; 124; 187–215. [DOI] [PubMed]
  • 28).Everitta A, Meites J. Aging and antiaging effects of hormones. J. Gerontol. 1989; 44: B139–147. [DOI] [PubMed]
  • 29).Sapolsky RM. Do glucocorticoid concentrations rise with age in the rat? Neurobiol. Aging 1992; 13, 171–174. [DOI] [PubMed]
  • 30).Kizaki T, Yamashita H, Oh-ishi S, Day NK, Good RA, Ohno H. Immunomodulation by cells of mononuclear phagocyte lineage in acute cold-stressed or cold-acclimatized mice. Immunology 1995; 86: 456–462. [PMC free article] [PubMed]
  • 31).Kizaki T, Kobayashi S, Ogasawara K, Day NK, Good RA, Onoé K. Immune suppression induced by protoscoleces on Echinococcus multilocularis in mice.: Evidence for the presence of CD8dull suppressor cells in spleens of mice intraperitoneally infected with E. multilocularis. J. Immunol. 1991; 147: 1659–1666. [PubMed]
  • 32).Kizaki T, Ishige M, Bingyan W, Day NK, Good RA, Onoe K. Generation of CD8+ suppressor T cells by protoscoleces of Echinococcus multilocularis in vitro. Immunology 1993; 79: 412–417. [PMC free article] [PubMed]
  • 33).Kizaki T, Ishige M, Bingyan W, Kumagai M, Day NK, Good RA, Onoé K. Interleukin-1-dependent mitogenic responses induced by protoscoleces of Echinococcus multilocularis in murine lymphocytes. J. Leukocyte Biol. 1993; 53: 233–239. [DOI] [PubMed]
  • 34).Kizaki T, Ishige M, Kobayashi S, Bingyan W, Kumagai M, Day NK, Good RA, Onoé K. Suppression of T-cell proliferation by CD8+ T cells induced in the presence of protoscolices of Echinococcus multilocularis in vitro. Infect. Immun. 1993; 61: 525–533. [DOI] [PMC free article] [PubMed]
  • 35).Kizaki T, Oh-ishi S, Ohno H. Acute cold stress induces suppressor macrophages in mice. J. Appl. Physiol. 1996; 81: 393–399. [DOI] [PubMed]
  • 36).Fujiwara R, Tanaka N, Orita K. Suppressive influence of surgical stress on the graft-versus-host reaction in mice. Acta Med. Okayama 1985; 38: 439–446. [DOI] [PubMed]
  • 37).Hibbs JB Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 1987; 235: 473–476. [DOI] [PubMed]
  • 38).Stuehr DJ, Nathan CF. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med. 1989; 169: 1543–1555. [DOI] [PMC free article] [PubMed]
  • 39).Schleifer KW, Mansfield JM. Suppressor macrophages in African Trypanosomiasis inhibit T cell proliferative responses by nitiric oxide and prostaglandins. J. Immunol. 1993; 151: 5492–5503. [PubMed]
  • 40).Kizaki T, Oh-ishi S, Ookawara, Yamamoto M, Izawa T, Ohno H. Glucocorticoid-mediated generation of suppressor macrophages with high density FcγRII during acute cold stress. Endocrinology 1996; 137: 4260–4267. [DOI] [PubMed]
  • 41).Allison AC, Mansfield JM. Mechanisms by which activated macrophages inhibit lymphocyte responses. Immunol. Rev. 1978; 40: 1–26. [DOI] [PubMed]
  • 42).Ravetch JV. Fc receptors: Rubor redux. Cell 1994; 78: 553–560. [DOI] [PubMed]
  • 43).Alen JM, Seed B. Isolation and expression of functional high-affinity Fc receptor complementary DNAs. Science 1989; 243: 378–381. [DOI] [PubMed]
  • 44).Choquet D, Prtiseti M, Amigorena S, Bonnerot C, Fridman WH, Korn H. Cross-linking of IgG receptors membrane immunoglobulin-stimulated calcium influx in B lymphocytes. J. Cell Biol. 1993; 121: 355–363. [DOI] [PMC free article] [PubMed]
  • 45).Muta T, Kurosaki T, Mlsulovin Z, Sanchez M, Nussenzweig MC, Ravetch JV. A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling. Nature 1994; 368: 70–73. [DOI] [PubMed]
  • 46).Pani G, Kozlowski M, Cambier JC, Mills GB, Siminovitch KA. Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J. Exp. Med. 1995; 181: 2077–2084. [DOI] [PMC free article] [PubMed]
  • 47).Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV. Augmented humoral and anaphylactic responses in FcγRII-deficient mice. Nature 1996; 379: 346–349. [DOI] [PubMed]
  • 48).Ckanab HM. Corticosteroids and lymphoid cells. N. Engl. J. Med. 1972; 287: 388–394. [DOI] [PubMed]
  • 49).Cupps TR, Fauci AS. Corticosteroid-mediated immunoregulation in man. Immunol. Rev. 1982; 65: 133–155. [DOI] [PubMed]
  • 50).Chowers I, Conforti N, Feldman S. Effect of changing levels of glucocorticosteroids on body temperature on exposure to cold. Am. J. Physiol. 1970; 218: 1563–1567. [DOI] [PubMed]
  • 51).Hayashi O, Kikuchi M. Time relationship between ambient temperature change and antigen stimulation on immune responses of mice. Int. J. Biometeol. 1989; 33: 19–23. [DOI] [PubMed]
  • 52).Warren MK, Vogel SN. Opposing effects of glucocorticoids on interferon-γ-induced murine macrophage Fc receptor and la antigen expression. J. Immunol. 1985; 134: 2462–2469. [PubMed]
  • 53).Girard MT, Hjaltadottir S, Fejes-Toth AN, Guyre PM. Glucocorticoids enhance the γ-interferon augmentation of human monocyte immunoglobulin G receptor expression. J. Immunol. 1987; 138: 3235–3241. [PubMed]
  • 54).Helmberg A, Fassler R, Geley S, Johrer K, Kroemer G, Bock G, Kofler R. Glucocorticoid-regulated gene expression in the immune system: Analysis of glucocorticoid-regulated transcripts from the mouse macrophage-like cell line P388D1. J. Immunol. 1990; 145; 4332–4337. [PubMed]
  • 55).Kizaki T, Haga S, Sakata I, Ookawara T, Segawa M, Sakurai T, Izawa T, Ohno H. Swimming training prevents generation of suppressor macropages during acute cold stress. Med. Sci. Sports Exerc. 2000; 32: 143–148. [DOI] [PubMed]
  • 56).Kizaki T, Ookawara T, Izawa T, Nagasawa J, Haga S, Radák Z, Ohno H. Relationship between cold tolerance and generation of suppressor macrophages during acute cold stress. J. Appl. Physiol. 1997; 83: 1116–1122. [DOI] [PubMed]
  • 57).Ohno H, Kizaki T, Ohishi S, Yamashita H, Tanaka J, Gasa S. Effects of swimming training on the lysosomal enzyme system in brown adipose tissue of rats: an analogy between swimming exercise and cold acclimation. Acta Physiol. Scand. 1995; 155: 333–334. [DOI] [PubMed]
  • 58).Cox RH. Exercise training and response to stress; insights from an animal model. Med. Sci. Sports Exere. 1991; 23: 853–859. [PubMed]
  • 59).Roth D, Holmes D. Influence of physical fitness in determining impact of stressful life events in physical and psychological health. Psychosom. Med. 1985; 47: 164–173. [DOI] [PubMed]
  • 60).Raglin JS, Morgan WP. Influence of vigorous exercise on mood state. Behav. Ther. 1985; 8: 179–183.
  • 61).Sutton JR, Brown GE, Keane P, Walker WHC, Jones NL, Rosenbloom D, Bessier GM. The role of endorphins in the hormonal and psychological responses to exercise. Int. J. Sports Med. 1982; 2: 19–23.
  • 62).Cooksey JD, Reilly P, Brownk S, Bromze H, Cryer P. Exercise training and plasma catecholamines in patients with ishemic heart disease. Am. J. Cardiol. 1978; 42: 372–376. [DOI] [PubMed]
  • 63).Chao CC, Strgar F, Tsang M, Peterson PK. Effects of swimming exercise on the pathogenesis of acute murine toxoplasma gondii Me49 infection. Clin. Immunol. Immunopathol. 1992; 62: 220–226. [DOI] [PubMed]
  • 64).Gilmore W, Molony M, Weiner LP. The role of opioid peptides in immunomodulation. Ann. N.Y. Acad. Sci. 1990; 597: 252–263. [DOI] [PubMed]
  • 65).Kizaki T, Suzuki K, Hitomi Y, Iwabuchi K, Onoé K, Ishida H, Izawa T, Ji LL, Ohno H. Activation and apoptosis of murine peritoneal macrophages by acute cold stress. Biochem. Biophys. Res. Commun. 2001; 283: 700–706. [DOI] [PubMed]
  • 66).Iwabuchi K, Hatakeyama S, Takahashi A, Ato M, Okada M, Kajino Y, Kajino K, Ogasawara K, Takami K, Nakagawa H, Onoé K. Sck overexpression reduces several monokine and nitric oxide productions but enhances prostaglandin E2 in response to lipopolysaccharide in the macrophage cell line J774A.1. Eur. J. Immunol. 1997; 27: 742–749. [DOI] [PubMed]
  • 67).Hatakeyama S, Iwabuchi K, Ogasawara K, Good RA, Onoé K. The murine c-fgr gene product associated with Ly6C and p70 integral membrane protein is expressed in cells of a monocyte/macrophage lineage. Proc. Natl. Acad. Sci. USA 1994; 91: 3458–3462. [DOI] [PMC free article] [PubMed]
  • 68).Kizaki T, Suzuki K, Iwabuchi I, Onoé K, Haga S, Ishida H, Ookawara T, Suzuki K, Ohno H. Negative regulation of LPS-stimulated expression of inducible nitric oxide synthase by AP-1 in macrophage cell line J774A.1. Biochem. Biophys. Res. Commun. (in press). [DOI] [PubMed]
  • 69).Clynes R, Maizes J, Guinamard R, Ono M, Takai T, Ravetch J. Modulation of immune complex-induced inflammation in vivo by the co-ordinate expression of activation and inhibiting Fc receptors. J. Exp. Med. 1999; 189: 179–185. [DOI] [PMC free article] [PubMed]
  • 70).Dang H, Geiser AG, Letterio JJ, Nakabayashi T, Kong L, Fernandes G, Talal N. SLE-like autoantibodies and Sjogren's syndrome-like lymphoproliferation in TGFβ knckout mice. J. Immunol. 1995; 155: 3205–3212. [PubMed]
  • 71).Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin 10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263–274. [DOI] [PubMed]
  • 72).Medvedev AE, Kopydlowski KM, Vogel SN. Inhibition of lipopolysaccharide-induced signal transduction in endotixin-tolerized mouse macrophages: Dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. J. Immunol. 2000; 164: 5564–5574. [DOI] [PubMed]
  • 73).Kizaki T, Ookawara T, Oh-ishi S, Itoh Y, Iwabuchi K, Onoé K, Day NK, Good RA, Ohno H. An increase in basal glucocorticoid concentration with age induces suppressor macrophages with high-density FcγRII/III. Immunology 1998; 93, 409–414. [DOI] [PMC free article] [PubMed]
  • 74).Gottensman SRS, Thorbecke GJ, Walford RL. Specific and non-specific suppressor cells in aged animals. In: Aging and the Immune System. Goidl EA editor. New York, Marcel Dekker. 1987: 243.
  • 75).Chorincha BB, Kong L-Y, Mao L, Mccallum E. Age-associated differences in TNF-α and nitric oxide production in endotoxic mice. J. Immunol. 1996; 156: 1525–1530. [PubMed]
  • 76).Chen LC, Pace JL, Russell SW, Morrison DC. Altered regulation of inducible nitric oxide synthase expression in macrophages from senescent mice. Infect. Immun. 1996; 64: 4288–4298. [DOI] [PMC free article] [PubMed]
  • 77).Kizaki T, Ookawara T, Iwabuchi K, Onoé K, Day, NK, Good RA, Maruyama N, Haga S, Matsuura N, Ohira Y, Ohno H. Age-associated increase of basal corticosterone levels decreases ED2high, NF-κBhigh activated macrophages. J. Leukocyte Biol. 2000; 68: 21–30. [PubMed]
  • 78).Kizaki T, Ookawara T, Haga S, Matsuura N, Ohno H. Effects of ageing on generation of ED2high major histocompatibility complex class II+ macrophages during cold stress. Scand. J. Immunol. 2000; 51: 36–44. [DOI] [PubMed]
  • 79).Barbé E, Damoiseaux JGMC, Döpp EA, Dijkstra CD. Characterization and expression of the antigen present on resident rat macrophages recognized by monoclonal antibody ED2. Immunobiology 1990; 182: 88–99. [DOI] [PubMed]
  • 80).Ray A, Prefontaine KE. Physical association and functional antagonism between the p65 subunit of transcription factor NFκB and the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA 1994; 91: 752–756. [DOI] [PMC free article] [PubMed]
  • 81).Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS. Characterization of Mechanisms involved in transrepression of NFκB by activated glucocorticoid receptors. Mol. Cell Biol. 1995; 15: 943–953. [DOI] [PMC free article] [PubMed]
  • 82).Scheinman RI, Cogswell PC, Lofquist AK, Baldwin Jr AS. Role of Transcriptional activation of IκB in mediation of Immunosuppression by glucocorticoids. Science 1995; 270: 283–286. [DOI] [PubMed]
  • 83).Auphan N, Didonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glcocorticoids: inhibition of NFκB activity through induction of IκB synthesis. Science 1995; 270: 286–290. [DOI] [PubMed]
  • 84).Brostjan C, Anrther J, Csizmadia V, Stroka D, Soares M, Bach FH, Winkler H. Glucocorticoid-mediated repression of NFκB activity in endothelial cells does not involve induction of IκBα synthesis. J. Biol. Chem. 1996; 271: 19612–19616. [DOI] [PubMed]
  • 85).De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, Haegeman G. Glucocorticoid-mediated repression of nuclear factor-κB-dependent transcription involves direct interference with transactivation. Proc. Natl. Acad. Sci. USA 1997; 94: 13504–13509. [DOI] [PMC free article] [PubMed]
  • 86).Heck S, Bender K, Kullmann M, Göttlicher M, Herrlich P, Cato ACB. IκB-independent downregulation of NFκB activity by glucocorticoid receptor. EMBO J. 1997; 16: 4698–4707. [DOI] [PMC free article] [PubMed]
  • 87).Eisen LP, Elsasser MS, Harmon JM. Positive regulation of the glucocorticoid receptor in human T-cells sensitive to the cytolytic effects of glucocorticoid. J. Biol. Chem. 1988; 263: 12044–12048. [PubMed]
  • 88).Ray A, Prefontaine KE. Physical association and functional antagonism between the p65 subunit of transcription factor NFκB and the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA 1994; 91: 752–756. [DOI] [PMC free article] [PubMed]
  • 89).Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS. Characterization of Mechanisms involved in transrepression of NFκB by activated glucocorticoid receptors. Mol. Cell Biol. 1995; 15: 943–953. [DOI] [PMC free article] [PubMed]
  • 90).Karp CL, Wysocka M, Ma X, Marovich M, Factor RE, Nutman T, Armant M, Wahl L, Cuomo P, Trinchieri G. Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance. Eur. J. Immunol. 1998; 28: 3128–3136. [DOI] [PubMed]
  • 91).Medzhitov R, Janeway CA Jr. Innate immunity: impacto on the adaptive immune response. Curr. Opin. Immunol. 1997; 9: 4–9. [DOI] [PubMed]
  • 92).Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91: 295–298. [DOI] [PubMed]
  • 93).Berinardini R, Mauceri G, Iurata M, Chiarenza A, Lempereur L, Sacpagnini U. Response of the hypothalamic-pituitary-adrenal axis to interleukin 1 in the aging rat. Prog. Neuro Endocrin Immunol. 1992; 5: 166–171.
  • 94).Mune A, Guyre P, Holbrook N. Physiological functions of glucocorticoids during stress and their relation to pharmacological actions. Endocr. Rev. 1984; 5: 25–44. [DOI] [PubMed]
  • 95).Stein-Behrens BA, Sapolsky RM. Stress, glucocorticoids, and aging. Aging Clim. Exp. Res. 1992; 4: 197–210. [DOI] [PubMed]

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