Anti‐inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro

Abstract

Corticosteroids (CS) and norepinephrine (NE) support each other's biological effects. Thus, deficiency of cortisol and reduced synovial sympathetic innervation (SSI) may be proinflammatory in rheumatoid arthritis (RA). This study tested the anti-inflammatory cooperativity of CS and NE in human RA synovial tissue. In an in vivo study, 32 patients with RA (with prior CS therapy/without SSI: n=7; without prior CS therapy/with SSI: 6; with prior CS therapy/with SSI: 19) were investigated for synovial inflammation. In an in vitro study with synoviocytes from RA and OA patients, the separate and combined effects of cortisol and NE were studied. In the in vivo study, patients with prior CS therapy/with SSI showed lower secretion of synovial IL-8 than the other groups, lower synovial density of T cells and macrophages, and lower overall inflammation. In the in vitro study, a cooperative suppressive effect of NE (10(-6) M to 10(-8) M) and cortisol (10(-6) M and 10(-7) M) on secretion of IL-8 and TNF from primary early culture mixed RA synoviocytes was observed. This cooperative effect was not observed in OA synoviocytes. In the same RA and OA patients, the cooperative effect was lost in 3rd passage synovial fibroblasts. This study demonstrates the cooperativity of cortisol and NE for inhibition of proinflammatory mediators produced in the synovial tissue of RA patients. These results underscore that coupling of an efficient secretion of systemic cortisol together with local production of NE is important in order to lower synovial inflammation.

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“…The point of transition for these differential effects is approximately 10 -7 mol/l for serum cortisol and norepinephrine in the tissue. Finally, release of cortisol is coupled to release of norepinephrine, which leads to stronger signaling through the ␤ -adrenoceptor (leading to cooperativity of cortisol and norepinephrine) [25] . However, the question appears whether or not stress axes are intact in patients with RA.…”

Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

“…Cortisol and norepinephrine act synergistically, increasing glucocorticoid receptors, b-adrenoceptors, and intracellular mediators in different cell types (3,4), thereby inducing an anti-inflammatory response (5,6). Norepinephrine recognizes membrane receptors (a-and b-adrenoceptors) on cells implicated in the immune response.…”

A Animal Study of Immunohistochemical Analysis of Sympathetic Nerve Fibers in Osteonecrosis of Femoral Head in Comparison with Osteoarthritis

“…The asthma therapy is known that both drugs act synergistically. Straub et al [21] showed that the serum levels of both cortisol and norepinephrine in rheumatoid arthritis patients are low, whereas the levels of IL-6 and TNF are elevated, suggesting a generalized inflammatory response [21]. A bony inflammatory response would also explain why early stages of a scintigraphy can represent using technetium 99m mAb [4].…”