Anti-Inflammatory Effects Of Tyrosine-Hydroxylase(TH)-Positive Catecholamine Producing Cells In Chronic Arthritis

Zsuzsa Jenei-Lanzl¹, Silvia Capellino², Frieder Kees³ and Rainer H. Straub⁴, ¹Department of Internal Medicine, University Hospital Regensburg, 1Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Regensburg, Germany, ²2Department of Pediatrics, Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA., Baltimore, MD, ³Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany, ⁴Department of Internal Medicine I, Laboratory of Exp. Rheumatology and Neuroendocrino-Immunology, University Hospital of Regensburg, Regensburg, Germany

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Catecholamines, Cell therapy, cytokines and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Animal Models I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

In previous studies we have shown that inflammatory processes in experimental arthritis are strongly affected by the sympathetic nervous system (SNS): In the early acute phase SNS acts proinflammatory, whereas in the late chronic phase anti-inflammatory. At the beginning of the chronic phase, the loss of sympathetic nerve fibers in synovial tissue was reported, which is paralleled by appearance of tyrosine-hydroxylase-positive (TH+) catecholamine-producing cells. Recently, TH+ cells of rheumatoid arthritis (RA) and osteoarthritis (OA) patients have been shown to exhibit anti-inflammatory properties in vitro. In addition, it is known that the microenvironment of inflamed joints is hypoxic and that hypoxia induces tyrosine hydroxylase (TH) in vivo. However, further important cofactors and inducers of this catecholamine-producing enzyme have never been studied and the role of TH+ cells in vivo is not yet known.

Methods:

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, TH activity, 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 (MSC) by a defined dopaminergic factors.

Results:

Hypoxia increased TH protein expression, TH enzyme activity, 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 (αMPT). Incubation with specific TH cofactors tetrahydrobiopterin (BH₄) and iron (Fe²⁺) increased hypoxia-induced inhibition of TNF, which was also reversed by αMPT. The success of TH+ cell generation from murine MSCs was confirmed by detetction of neuronal/dopaminergic markers. Adoptive transfer of TH+ cells reduced CIA score in mice significantly, and 6 hydroxydopamine, which depletes TH+ cells, was able to reverse this effect (Fig.1).

Conclusion:

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 on experimental arthritis in mice has been presented. Using generated TH+ cells might open new avenues for cellular arthritis therapy.

Disclosure:

Z. Jenei-Lanzl,
None;

S. Capellino,
None;

F. Kees,
None;

R. H. Straub,
None.

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