Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids Vinicius F. Carvalho, Emiliano O. Barreto, Bruno L. Diaz, Magda F. Serra, Viviane Azevedo, Renato S.B. Cordeiro, Marco A. Martins, Patrı ´cia M.R. e Silva * Laborato ´rio de Inflamac ßa ˜o, Departamento de Fisiologia e Farmacodina ˆmica, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil, no. 4365, Manguinhos, CEP 21045-900, Rio de Janeiro, Brazil Received 6 January 2003; received in revised form 21 May 2003; accepted 26 May 2003 Abstract This study was undertaken to examine whether glucocorticoids could be implicated in the hyporesponsiveness of diabetic rats to systemic anaphylaxis. Rats were actively sensitized with a mixture of Al(OH) 3 plus ovalbumin and challenged i.v. with ovalbumin 14 days later. Diabetes was induced by alloxan-injected i.v. either before or after sensitization. Elevation of total and specific serum immunoglobulin E (IgE) was abolished in rats turned diabetic and then sensitised, but not in those first sensitised and then turned diabetic. In both conditions, increased serum corticosterone levels occurred in parallel with protection of diabetic animals against fatal shock, intestinal haemorrhage and elevation in plasma histamine levels evoked by antigen challenge. The resistance of diabetic rats to fatal shock was no longer significantly different from that of non-diabetic rats following treatment with the glucocorticoid receptor antagonist RU 486 (mifepristone). These findings indicate that endogenous glucocorticoid plays a pivotal role in the phenomenon of hyporeactivity to systemic anaphylaxis in alloxan-diabetic rats. D 2003 Elsevier B.V. All rights reserved. Keywords: Diabetes; Systemic anaphylaxis; Glucocorticoid; Mast cell 1. Introduction It has been demonstrated that diabetic patients present many functional abnormalities which can be partially re- sponsible for their failure in mounting a plain inflammatory response (Garcia-Leme, 1989). In line with this concept, some authors reported that the concurrent occurrence of allergic disorders and type 1 diabetes is markedly reduced when compared to the incidence of each one alone (Huang, 1999; Olesen et al., 2001). This observation was made many years ago but the precise mechanism is not yet understood. The possibility does exist that the resistance to allergic provocation results from an imbalance in the T-helper 1/T- helper 2 (Th1/Th2) response. Since autoimmune type 1 diabetes is Th1-dependent and allergy is Th2-dependent, the susceptibility to one disease might lead a state of refractoriness to the other (Huang, 1999). Systemic anaphylaxis is an acute and often life-threat- ening reaction which results from the immediate release of pro-inflammatory substances when the allergen interacts with immunoglobulin E (IgE) antibodies anchored on the surface of mast cells or basophils (Busse and Lemanske, 2001; Kay, 2001). Earlier studies demonstrated that allox- an-diabetic mice were resistant to anaphylactic shock (Thompson, 1961; Ganley, 1962; Dhar et al., 1967; Ptak et al., 1983), in a mechanism clearly reversed by treatment with insulin (Thompson, 1961; Ganley, 1962). Interesting- ly, insulin administration before antigen challenge increased the mortality from anaphylactic shock in actively sensitized rodents (Ptak et al., 1983). One potential explanation for this phenomenon is that the resistance of diabetic animals to anaphylactic reactions is due to an excess of glucose in the blood circulation. Indeed, a marked protection was noted under the condition of hyperglycaemia induced by a massive dose of glucose administered before antigen provocation (Ptak et al., 1983). Another possibility is that insulin depletion may prevent the triggering of IgE-produc- ing cells or decrease the rate of IgE production, which would be associated with T or B cell defects. In fact, the 0014-2999/03/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0014-2999(03)01934-4 * Corresponding author. Tel.: +55-21-2562-0818; fax: +55-21-2558- 7382. E-mail address: patmar@ioc.fiocruz.br (P.M.R. e Silva). www.elsevier.com/locate/ejphar European Journal of Pharmacology 472 (2003) 221 – 227