Logo of brjpharmLink to Publisher's site
Br J Pharmacol. 1996 Apr; 117(7): 1530–1534.
PMCID: PMC1909448

Regulation of tumour necrosis factor production by adrenal hormones in vivo: insights into the antiinflammatory activity of rolipram.


1. The role of adrenal hormones in the regulation of the systemic and local production of tumour necrosis factor (TNF alpha) was examined in male Balb/c mice. 2. Intraperitoneal injection of 0.3 mg E. coli lipopolysaccharide (LPS, 0111:B4) led to high levels of circulating TNF alpha without stimulating TNF alpha production in the peritoneal cavity. Systemic production of TNF alpha in response to LPS was increased in adrenalectomized animals and in normal animals treated with the beta-adrenoceptor antagonist, propranolol. The glucocorticoid antagonist, RU 486, did not modify systemic TNF alpha production. These results indicate that systemic TNF alpha production is regulated by adrenaline but not by corticosterone. 3. When mice were primed with thioglycollate, TNF alpha was produced in the peritoneal cavity in response to low dose LPS (1 micrograms). The levels of TNF alpha in the peritoneal cavity were not enhanced by adrenalectomy or by treatment with either propranolol or RU 486, indicating local production of TNF alpha in the peritoneal cavity is not regulated by adrenaline or corticosterone. 4. The phosphodiesterase type IV (PDE-IV) inhibitor, rolipram, inhibited both the systemic production of TNF alpha in response to high dose endotoxin (ED50 = 1.3 mg kg-1) and the local production of TNF alpha in the peritoneal cavity in response to low dose endotoxin (ED50 = 9.1 mg kg-1). In adrenalectomized mice there was a slight reduction in the ability of rolipram to inhibit the systemic production of TNF alpha (ED50 = 3.3 mg kg-1) while the ability of rolipram to inhibit the local production of TNF alpha in the peritoneal cavity was virtually abolished (24% inhibition at 30 mg kg-1). The glucocorticoid antagonist, RU 486, also reduced the ability of rolipram to inhibit local TNF alpha production while propranolol was without effect. 5. Systemic treatment with rolipram increased the plasma concentrations of corticosterone in normal mice but not in adrenalectomized mice indicating that rolipram can cause adrenal stimulation in vivo. 6. In summary, these data indicate that systemic production of TNF alpha in response to high dose endotoxin is controlled differently from the local production of TNF alpha in response to low dose endotoxin. The systemic production of TNF alpha is regulated by catecholamines, but not by corticosterone, while the local production of TNF alpha in the peritoneal cavity is not regulated by basal levels of either catecholamines or corticosterone. 7. These data also show that the ability of rolipram to inhibit the local production of TNF alpha is dependent on the release of corticosterone from the adrenal glands.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (965K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bailly S, Ferrua B, Fay M, Gougerot-Pocidalo MA. Differential regulation of IL 6, IL 1 A, IL 1 beta and TNF alpha production in LPS-stimulated human monocytes: role of cyclic AMP. Cytokine. 1990 May;2(3):205–210. [PubMed]
  • Beavo JA, Reifsnyder DH. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990 Apr;11(4):150–155. [PubMed]
  • Bertini R, Bianchi M, Ghezzi P. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med. 1988 May 1;167(5):1708–1712. [PMC free article] [PubMed]
  • Butler LD, Layman NK, Riedl PE, Cain RL, Shellhaas J, Evans GF, Zuckerman SH. Neuroendocrine regulation of in vivo cytokine production and effects: I. In vivo regulatory networks involving the neuroendocrine system, interleukin-1 and tumor necrosis factor-alpha. J Neuroimmunol. 1989 Sep;24(1-2):143–153. [PubMed]
  • Dent G, Giembycz MA, Rabe KF, Barnes PJ. Inhibition of eosinophil cyclic nucleotide PDE activity and opsonised zymosan-stimulated respiratory burst by 'type IV'-selective PDE inhibitors. Br J Pharmacol. 1991 Jun;103(2):1339–1346. [PMC free article] [PubMed]
  • Derkx B, Taminiau J, Radema S, Stronkhorst A, Wortel C, Tytgat G, van Deventer S. Tumour-necrosis-factor antibody treatment in Crohn's disease. Lancet. 1993 Jul 17;342(8864):173–174. [PubMed]
  • Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994 Oct 22;344(8930):1105–1110. [PubMed]
  • Flower RJ, Parente L, Persico P, Salmon JA. A comparison of the acute inflammatory response in adrenalectomised and sham-operated rats. Br J Pharmacol. 1986 Jan;87(1):57–62. [PMC free article] [PubMed]
  • Griswold DE, Webb EF, Breton J, White JR, Marshall PJ, Torphy TJ. Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response. Inflammation. 1993 Jun;17(3):333–344. [PubMed]
  • Hawes AS, Rock CS, Keogh CV, Lowry SF, Calvano SE. In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin. Infect Immun. 1992 Jul;60(7):2641–2647. [PMC free article] [PubMed]
  • Nielson CP, Vestal RE, Sturm RJ, Heaslip R. Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst. J Allergy Clin Immunol. 1990 Nov;86(5):801–808. [PubMed]
  • Parant M, Le Contel C, Parant F, Chedid L. Influence of endogenous glucocorticoid on endotoxin-induced production of circulating TNF-alpha. Lymphokine Cytokine Res. 1991 Aug;10(4):265–271. [PubMed]
  • Peachell PT, Undem BJ, Schleimer RP, MacGlashan DW, Jr, Lichtenstein LM, Cieslinski LB, Torphy TJ. Preliminary identification and role of phosphodiesterase isozymes in human basophils. J Immunol. 1992 Apr 15;148(8):2503–2510. [PubMed]
  • Peers SH, Moon D, Flower RJ. Reversal of the anti-inflammatory effects of dexamethasone by the glucocorticoid antagonist RU 38486. Biochem Pharmacol. 1988 Feb 1;37(3):556–557. [PubMed]
  • Perretti M, Becherucci C, Scapigliati G, Parente L. The effect of adrenalectomy on interleukin-1 release in vitro and in vivo. Br J Pharmacol. 1989 Dec;98(4):1137–1142. [PMC free article] [PubMed]
  • Perretti M, Duncan GS, Flower RJ, Peers SH. Serum corticosterone, interleukin-1 and tumour necrosis factor in rat experimental endotoxaemia: comparison between Lewis and Wistar strains. Br J Pharmacol. 1993 Oct;110(2):868–874. [PMC free article] [PubMed]
  • Pettipher ER, Wimberly DJ. Cyclooxygenase inhibitors enhance tumour necrosis factor production and mortality in murine endotoxic shock. Cytokine. 1994 Sep;6(5):500–503. [PubMed]
  • Sekut L, Yarnall D, Stimpson SA, Noel LS, Bateman-Fite R, Clark RL, Brackeen MF, Menius JA, Jr, Connolly KM. Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Clin Exp Immunol. 1995 Apr;100(1):126–132. [PMC free article] [PubMed]
  • Semmler J, Wachtel H, Endres S. The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int J Immunopharmacol. 1993 Apr;15(3):409–413. [PubMed]
  • Severn A, Rapson NT, Hunter CA, Liew FY. Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists. J Immunol. 1992 Jun 1;148(11):3441–3445. [PubMed]
  • Simpson PJ, Schelm JA, Smallwood JK, Clay MP, Lindstrom TD. Inhibition of granulocyte cAMP-phosphodiesterase by rolipram in vivo is not sufficient to protect the canine myocardium from reperfusion injury. J Cardiovasc Pharmacol. 1992 Jun;19(6):987–995. [PubMed]
  • Sommer N, Löschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmüller A, Fontana A, et al. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med. 1995 Mar;1(3):244–248. [PubMed]
  • Turner CR, Esser KM, Wheeldon EB. Therapeutic intervention in a rat model of ARDS: IV. Phosphodiesterase IV inhibition. Circ Shock. 1993 Mar;39(3):237–245. [PubMed]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...