There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by intravenous injection of lipopolysaccharide results in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes are accompanied by an induced production of IL-1 and IL-1 receptor type 1, as well as of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E₂ production in the adrenals, which also displayed EP₁ and EP₃ receptors in the cortex and medulla. The IL-1 expression was also induced by systemically administrated IL-1 and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1 similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was in contrast further enhanced by IL-1 receptor antagonist. These data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals' response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.