Anti-inflammatory activity of salmeterol: down-regulation of cytokine production

Abstract

SUMMARYElevation of intracellular cAMP levels has been shown previously to inhibit cytokine secretion by various cell types in vitro. Since salmeterol is a /Jj-agonist which activates adenylate cyclase, its ability lo inhibit cytokine production was evaluated. Though salmeterol, and the related drug albuterol. did not inhibit IL-l/i produclion in vitro, both drugs did inhibit tumour necrosis factoralpha (TNF-a) secretion by lipopolysaccharide (LPS)-activated THP-1 cells with similar ICjoS of approximately OlyiM. This inhibition was effectively reversed by the /i2-antagonist oxprenolol, indicating that the inhibition was mediated through the ,tf2-adrenergic receptor. A strikingly different reactivity profile was seen with T cells. Salmeterol was able to inhibit the activation of both mouse and human Tcelis. as measured by proliferation and IL-2 secretion in response to anti-CD3 antibody, whereas albuterol was completely inactive in these assays. This T cell inhibition by salmeterol was about 10-fold less potent than that for TNF-a production, and was not reversed by a /32-antagonist, indicating thai a different mechanism was involved in the effect of salmeterol on T cells. Paralleling the TNF-a inhibitory activity in vitro, oral dosing of salmeterol and albuterol inhibited LPS-induced increase in murine serum TNF level in vivo, with EDsos of approximately 01 mg/kg. This inhibition could be abrogated by dosing orally with the /^blocker propranolol. The long-acting pharmacological profile of salmeterol was apparent in that it maintained its efficacy for 3h. while albuterol had a much shorter duration of action. Salmeterol also had some protective effects in the galactosamine/LPS model of endotoxic shock, which is dependent upon TNF-a production. Though satmeterol inhibited serum TNF-a levels by up to 94% in this assay, it protected less than 50% ofthe animals from the lethal effects ofthe LPS/gal actosa mine mixture. This observation suggests that functional levels of TNF-a localized in tissues may not be accurately reflected by serum levels.

Beta-2-Adrenergic Receptor Regulates Insulin Signaling to Reduce Cell Death in Müller Cells

“…32 In rheumatoid arthritis, TNF-and another inflammatory marker, IL-1 are believed to be upregulated in T-cells. 33 Studies have shown that T-cells secrete IL-1 and TNF-in response to a stress in this condition. 33 Cyclic AMP and PKA decreases production of inflammatory cytokines T-cells.…”

“…33 Studies have shown that T-cells secrete IL-1 and TNF-in response to a stress in this condition. 33 Cyclic AMP and PKA decreases production of inflammatory cytokines T-cells. 33 Previous research has shown that signaling in rheumatoid arthritis is attributed to the beta-2 adrenergic receptor subtype.…”

“…33 Cyclic AMP and PKA decreases production of inflammatory cytokines T-cells. 33 Previous research has shown that signaling in rheumatoid arthritis is attributed to the beta-2 adrenergic receptor subtype. 33 Further studies suggest that treatment with a beta-2 adrenergic receptor agonist, salmeterol, is able to block T-cell activation, which blocks production of inflammatory markers TNF-and IL-1 .…”

“…33 Previous research has shown that signaling in rheumatoid arthritis is attributed to the beta-2 adrenergic receptor subtype. 33 Further studies suggest that treatment with a beta-2 adrenergic receptor agonist, salmeterol, is able to block T-cell activation, which blocks production of inflammatory markers TNF-and IL-1 . 33 In ocular inflammation, TNF-may be involved in induced uveitis, retinal degeneration, glaucoma, and diabetic retinopathy.…”

“…33 Further studies suggest that treatment with a beta-2 adrenergic receptor agonist, salmeterol, is able to block T-cell activation, which blocks production of inflammatory markers TNF-and IL-1 . 33 In ocular inflammation, TNF-may be involved in induced uveitis, retinal degeneration, glaucoma, and diabetic retinopathy. 34 Some of the effects of TNFinclude cellular apoptosis and crosstalk with other inflammatory markers, such as iNOS, ICAM-1, and prostaglandins.…”