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Systemic Immune Challenge Activates an Intrinsically Regulated Local Inflammatory Circuit in the Adrenal Gland

Department of Clinical and Experimental Medicine (L.E., K.R., A.A., A.F., L.M., D.E., A.B.), Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden; and Laboratory of Psychoneuroimmunology, Nutrition, and Genetics (J.P.K.), Centre National de Recherche Scientifique, Unité Mixte de Recherche 5226, Institut National de Recherche Agronomique, Unité Mixte de Recherche 1286, Université Bordeaux 2, 33076 Bordeaux, France

Address all correspondence and requests for reprints to: Dr. Anders Blomqvist, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden. E-mail: andbl{at}ibk.liu.se.

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 iv 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-1β and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E₂ production in the adrenals, which also displayed prostaglandin E₂ receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1β expression was also induced by systemically administrated IL-1β and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1β 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.

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