29. Anti-inflammatory effects of tyrosine-hydroxylase (TH)-positive catecholamine producing cells in chronic arthritis

Abstract

In previous studies we detected TH-positive, catecholamine-producing cells in inflamed hypoxic synovial tissue. Therefore, the aim of our study was to investigate the influence of hypoxia induced catecholamines on inflammatory responses in arthritis. Synovial cells of rheumatoid arthritis (RA) and osteoarthritis (OA) patients were isolated and cultivated under normoxia or hypoxia with/without stimulating enzyme cofactors of TH and inhibitors of TH. Expression of TH and release of cytokines and catecholamines was analyzed. The effect of TH+-cells was tested by adoptive transfer into DBA/1 mice with collagen type II – induced arthritis (CIA). TH+ cells were generated from mesenchymal stem cells by defined catecholaminergic factors. Hypoxia increased TH protein expression and catecholamine synthesis and decreased release of TNF in OA/RA synovial cells compared to normoxic conditions. This inhibitory effect on TNF was reversed by TH inhibition with alpha-methyl-para-tyrosine (alphaMPT). Incubation with specific TH cofactors (tetrahydrobiopterin and Fe2+) increased hypoxia-induced inhibition of TNF, which was also reversed by alphaMPT. Adoptive transfer of TH+ cells reduced CIA in mice, and 6 hydroxydopamine, which depletes TH+ cells, reversed this effect. In summary, this study presents that TH-dependent catecholamine synthesis exhibits anti-inflammatory effects in human RA synovial cells in vitro, which can be augmented under hypoxic conditions. In addition, the anti-inflammatory effect of TH+ cells has been presented the first time in experimental arthritis in mice.