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Stress activates the hypothalamic-pituitary-adrenal axis through release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down-regulate immune responses. Acute stress, however, also has proinflammatory effects that seem to be mediated through the activation of mast cells. Stress and mast cells have been implicated in the pathophysiology of various inflammatory conditions, including some in the central nervous system, such as multiple sclerosis in which disruption of the blood-brain barrier (BBB) precedes clinical symptoms. We previously showed that acute restraint stress increases rat BBB permeability to intravenous 99 Tc gluceptate and that administration of the "mast cell stabilizer" disodium cromoglycate (cromolyn) inhibits this effect. In this study, we show that the CRH-receptor antagonist Antalarmin blocks stress-induced 99 Tc extravasation, whereas site-specific injection of CRH in the paraventricular nucleus (PVN) of the hypothalamus mimics acute stress. This latter effect is blocked by pretreatment of the PVN with cromolyn; moreover, restraint stress cannot disrupt the BBB in the diencephalon and cerebellum of W/W v mast cell-deficient mice. These results demonstrate that CRH and mast cells are involved in regulating BBB permeability and, possibly, brain inflammatory disorders exacerbated by acute stress.

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Corticotropin releasing hormone (CRH) and interleukin-6 (IL-6) are implicated in inflammatory diseases triggered by stress. Acute restraint stress increases serum IL-6 in the blood, but its source is not known. Our current study was carried out in order to determine the contribution of mast cells to stressinduced IL-6 release and to investigate skin CRH and vascular permeability in mice. W /WY mast cell deficient and their wild type control +/+ mice were stressed in a plexiglass restraint chamber for 60 or 120 min. Serum corticosterone and IL-6 levels were measured. Other mice were injected with 99-Tchnetium gluceptate (99Tc) and its extravastion, indicating vascular permeability, was determined along with CRH levels in the skin and knee joints. Acute stress increased serum IL-6 in mice, but was greatly inhibited in W/WY mast cell deficient mice. Vascular permeability to 99Tc, as well as local CRH levels, were also increased by stress, but not in W!WY mice. Findings from our current study suggest a link between mast cells and stress-related skin and joint inflammation and may explain initial events in psoriatic and rheumatoid arthritis.

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