ag-490 and methyllycaconitine

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents; Caspase 3; Caspase Inhibitors; Central Nervous System Stimulants; Cholinergic Neurons; Colitis, Ulcerative; Colon; Dendritic Cells; Deoxyglucose; Disease Models, Animal; Enzyme Inhibitors; Janus Kinase 2; Mice, Inbred BALB C; Neuroimmunomodulation; Neuropeptides; Nicotine; Oxazolone; rac1 GTP-Binding Protein; STAT3 Transcription Factor; Th2 Cells; Tyrphostins; Vagus Nerve