Introduction Cannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects. The endocannabinoid receptor system, including the cannabinoid receptor 1 (CB 1 ) and receptor 2 (CB 2 ) and the endocannabinoids, are implicated in a wide range of physiological and pathophysiological processes. Pre-clinical and clinical studies have demonstrated that cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis. The aim of this study was to determine whether the key elements of the endocannabinoid signalling system, which produces immunosuppression and analgesia, are expressed in the synovia of patients with osteoarthritis (OA) or RA.

Aims To investigate the regulation of cannabinoid receptors CB1 and CB2 on immune cells by proinflammatory cytokines and its potential relevance to the inflammatory neurological disease, multiple sclerosis (MS). CB1 and CB2 signalling may be anti-inflammatory and neuroprotective in neuroinflammatory diseases. Cannabinoids can suppress inflammatory cytokines but the effects of these cytokines on CB1 and CB2 expression and function are unknown. Methods Immune cells from peripheral blood were obtained from healthy volunteers and patients with MS. Expression of CB1 and CB2 mRNA in whole blood cells, peripheral blood mononuclear cells (PBMC) and T cells was determined by quantitative real time-polymerase chain reaction (qRT-PCR). Expression of CB1 and CB2 protein was determined by flow cytometry. CB1 and CB2 signaling in PBMC was determined by Western blotting for Erk1/2. Results Proinflammatory cytokines IL-1β, IL-6 and TNF-α (the latter likely NFκB-dependently) can up-regulate CB1 and CB2 on human whole blood and peripheral blood mononuclear cells (PBMC). We also demonstrate up-regulation of CB1 and CB2 and increased IL-1β, IL-6 and TNF-α mRNA in blood of MS patients compared with controls. Conclusion The levels of CB1 and CB2 can be up-regulated by inflammatory cytokines, which can explain their increase in inflammatory conditions including MS.

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1 The b 2 -agonist salmeterol is a potent relaxant of airway smooth muscle with a long duration of action. Previous studies of cyclic AMP accumulation, however, have indicated that salmeterol is a low ecacy b 2 -agonist when compared to isoprenaline. Here we have compared the properties of salmeterol and isoprenaline as stimulants of gene transcription in CHO-K1 cells transfected with the human b 2 -adrenoceptor to dierent levels (50 and 310 fmol mg protein 71 ). 2 Gene transcription was monitored using a secreted placental alkaline phosphate (SPAP) reporter gene under the transcriptional control of six cyclic AMP response element (CRE) sequences. 3 In the lower expressing cells (CHO-b 2 /6), salmeterol produced a maximal cyclic AMP response that was only 22% that of that obtained with isoprenaline. In contrast in the higher expressing cells (CHO-b 2 / 4), the two maxima were of similar magnitude. 4 Salmeterol was a more potent stimulant of gene transcription, producing the same maximal response as isoprenaline in both cell lines. Furthermore, in the CHO-b 2 /4 cells, Salmeterol was 50 fold more potent as a stimulant of SPAP secretion than of cyclic AMP accumulation. In contrast, isoprenaline was 24 fold less sensitive as a stimulant of SPAP secretion than of cyclic AMP accumulation. In the presence of serum (10%), the eects of both salmeterol and isoprenaline on gene transcription were augmented. 5 These data suggest that the low ecacy and/or long duration of action of salmeterol, favours a potent stimulation of gene transcription when compared to more ecacious but shorter-lived agonists such as isoprenaline.