The present study provides the first direct evidence that implicates fish cytokines as the effector molecules by which the immune system signals the neuroendocrine system and activates the hypothalamic-pituitary-interrenal stress axis. I.p. injections of trout recombinant interleukin-1beta (rIL-1beta) or E. coli lipopolysaccharide (LPS), at concentrations known to induce immune/inflammatory responses in vivo (0.1-0.6 nmol/kg and 1.3 mg/kg respectively), significantly elevated plasma cortisol levels in a dose- and/or time-dependent manner. However, in contrast to general stress responses in fish, under the conditions employed in this study, no specific treatment effects on plasma glucose levels could be demonstrated. The trout IL-1beta peptides (P1 and P3), which are homologous to receptor-binding sequences of human IL-1beta, failed to influence the prevailing cortisol concentration even though an equivalent dose has been found to have immunostimulatoty properties in vivo. Blockade of endogenous ACTH release by administration of the synthetic glucocorticoid dexamethasone prevented the rIL-1beta/LPS-mediated elevation of plasma cortisol, suggesting that IL-1beta and LPS modulate cortisol secretion via effects at the level of the hypothalamic-pituitary axis. These data indicate that, with respect to IL-1beta, cytokine signalling between the immune and neuroendocrine systems in mammals appears to be conserved in lower vertebrates.