Tyrosine hydroxylase expression in CD4+ T cells is associated with joint inflammatory alleviation in collagen type II-induced arthritis

Abstract

We have recently reported that CD4(+) T cells synthesize and secrete catecholamines that facilitate a shift of T helper 1 (Th1)/Th2 balance toward Th2 polarization. In this study, we used an animal model of human rheumatoid arthritis, collagen type II-induced arthritis (CIA), to explore relationship between catecholamine production in CD4(+) T cells and Th1-/Th2-mediated joint inflammation. Histopathological observation of ankle joints of CIA mice displayed an evident inflammatory change on day 35 and a major damage to bones on day 55 post-immunization. Expression of Th1-specific transcription factor, T-bet, and cytokines, IL-2 and IFN-γ, and Th2-specific transcription factor, GATA-3, and cytokines, IL-4 and IL-10, was all upregulated on days 35 and 55 post-immunization, but the elevated Th1 response tended to decrease and the enhanced Th2 response tended to increase with the CIA progression. Expression of tyrosine hydroxylase (TH), a rate-limiting enzyme for synthesis of catecholamines, dramatically increased in ankle joints of CIA mice, although this increase was reduced on day 55 relative to that on day 35 post-immunization. In synovial tissue of CIA ankle joints but not normal joints, CD4-, T-bet-, GATA-3-, and TH-immunoreactive cells were found. Importantly, co-expressed cells with CD4 and TH, T-bet and TH, and GATA-3 and TH were observed in synovial tissue of CIA ankle joints. These results suggest that an increase in catecholamine production occurs in inflamed joints of CIA. The catecholamines are, at least in part, from Th1 and Th2 cells, and they may be related to joint inflammatory alleviation in CIA progression.

Expression of tyrosine hydroxylase in CD4+ T cells contributes to alleviation of Th17/Treg imbalance in collagen-induced arthritis

“…Previously, we have shown that the increased TH expression in inflamed synovial tissue of CIA ankle joints is attributed at least in part to Th1 and Th2 cells. 17 In this study, we found that IL-17/TH double-stained cells, but not CD25/TH double-stained cells, were increased in CD4 þ T cells of CIA mice. The findings provide further data showing that in addition to Th1 and Th2 cells, Th17 cells are also an important cell source of catecholamines in CD4 þ T cells of CIA mice.…”

“…It has become clear that balances between Th1 and Th2 cells, or their cytokines, are important in induction or prevention of RA. [15][16][17] Th17 cells are the newest member of the effector Th cell family and are characterized by high proinflammation via producing specific cytokines such as interleukin (IL)-17 and IL-22. 18,19 Treg cells are characterized by the control of immune responses to self and foreign antigens and by the suppression of harmful autoimmune T cells via producing anti-inflammatory cytokines such as transforming growth factor (TGF)-b.…”

“…Recently, we have shown that in inflammatory joints of CIA, TH expression in Th1 and Th2 cells is upregulated, suggesting that Th1 and Th2 cells may be a cell source of catecholamines in CIA joints. 17 However, it is unclear whether Th17 and Treg cells also produce catecholamines and what role the T cell-derived catecholamines play in CIA. We hypothesized that catecholamines derived from T cells, as ''sympathetic'' cells, may replace the locally lost sympathetic nerve fibers and exert a compensatory inhibition of Th17/Treg imbalance in CIA.…”

Immunomodulatory Effects Mediated by Dopamine

“…The enzymatic activity of TH and PAH in human leukocytes has been detected since the 1980s [ 112 – 114 ]. In addition, the expression and immunodetection of TH in human and mouse leukocytes have been widely reported [ 77 , 79 , 83 , 106 , 107 ]. On the other hand, DDC expression in human cells has also been documented [ 79 , 109 , 110 ] ( Table 1 ).…”

Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

“…CIA was induced for DBA/1 mice as described previously [ 35 , 36 ] with small modifications. Briefly, chicken collagen type II (CII, Sigma-Aldrich Co., USA) was dissolved at a concentration of 2 mg/mL in 0.1 M acetic acid and emulsified with an equal volume of complete Freund's adjuvant (Chondrex, Inc., USA).…”