The Role of the Adrenals in the Acute Phase Response to Interleukin-1 and Tumor Necrosis Factor-α

Abstract

The purpose of this study was to investigate the role of the adrenals, particularly the glucocorticoids, in the acute phase response following daily injections for 5 days of recombinant human interleukin-1α,β and tumor necrosis factor-α (TNFα). Adult weight-stable freely fed or pair-fed (to cytokine-injected mice) mice (C57B1/6J) with and without adrenals were used. Adrenalectomized animals showed a sensitivity to both IL-1α and -1β (40 ng IL-1/day) greater than 10- fold higher than that of normal mice (420 ng IL-1/day) in regard to mortality and anorexia. Microscopic examination of tissue specimens from adrenalectomized IL-1α,β-injected mice did not reveal any histologic alterations in lung, kidney, liver, brain, or gastrointestinal tract to explain the mortality. This mortality was not prevented by physiologic replacement doses of hydrocortisone (10-20 μg/day); however, a pharmacological dose of 2.5 mg hydrocortisone/day abolished completely the increased toxicity to IL-1α,β and the anorectic response to IL-1α,β and TNFα. Increased toxicity (mortality) was not observed in adrenalectomized animals with TNFα at the dose interval used (450 ng TNFα/day and lower). The hepatic acute phase response (liver weight and RNA and liver protein content) was increased by both IL-1α,β and TNFα in a glucocorticoid-independent way. The cytokine-induced alterations of plasma concentrations of acute phase proteins (serum amyoid P, transferrin, complement C3) were significantly dependent on glucocorticoids, while the decline in plasma albumin was not. Glucocorticoids acted as both a positive and a negative modulator of cytokine-regulated synthesis of individual plasma proteins. Plasma IL-6 was highest in mice with adrenals receiving IL-1α injections, significantly higher than that found in adrenalectomized animals. The results demonstrate that several acute phase responses to IL-1α,β and TNFα in the liver cells are independent of the presence of glucocorticoids, while several other reactions are either potentiated or attenuated by glucocorticoids. The increased toxicity to IL-1 in the absence of adrenals may contribute to the increased mortality at stress in patients with Addison's disease.