Methotrexate selectively modulates TH1/TH2 balance in active rheumatoid arthritis patients.
OBJECTIVE
The mechanism by which low dose methotrexate (MTX, the gold standard treatment for rheumatoid arthritis) exerts its anti-inflammatory effect in rheumatoid arthritis (RA) patients is still debated. Lately, the MTX immunosuppressive effect has been related to apoptosis, especially in active RA patients, with ROS involvement.


METHODS
In the present research we investigated MTX oxidative effect and its ability to modulate immune balance in active versus non-active RA patients.


RESULTS
Our results show that MTX induces IL-10 secretion (a TH2 cytokine) and significantly reduces TH1 profile in Peripheral Mononuclear Cells (PMNC) derived from active RA patients (n=28). Additionally, we found that MTX modulates the immune status towards TH2 dominance by decreasing the IL-12R and the CXCR3 receptors typical for the TH1 population. Moreover, MTX was found to inhibit the production of nitric oxide (NO) in these patients, a phenomenon that might contribute to MTX action toward cytokine homeostasis. A significant correlation was found between MTX IL-10 induction and NO inhibition in active RA patients.


CONCLUSIONS
Our data suggest that, in active RA patients, apoptosis induction by MTX may be primarily due to IL-10 production via modulation of oxidative stress, which may restore the critically important immune balance. These findings may contribute to determining which group of RA patients may better respond to MTX therapy.
Herman
S
S
The Biophysical Interdisciplinary Schottenstein Center for the Research and the Technology of the Cellome, Bar-Ilan University, Israel.
Zurgil
N
N
Langevitz
P
P
Ehrenfeld
M
M
Deutsch
M
M
D000208:Acute Disease; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D018501:Antirheumatic Agents; C515187:CXCR3 protein, human; D017382:Reactive Oxygen Species; D054367:Receptors, CXCR3; D053707:Receptors, Interleukin-12; D016753:Interleukin-10; D009569:Nitric Oxide; D008727:Methotrexate