Homocysteine enhances cytokine production in cultured synoviocytes from rheumatoid arthritis patients.
OBJECTIVE
Hyperhomocysteinemia is commonly observed in Rheumatoid Arthritis (RA) patients, thus putatively accounting in part for the high rate of cardiovascular events in these subjects. Homocysteine (Hcy) is known to exert a pro-inflammatory effect putatively contributing to the progression of atherosclerotic lesions by cytokine production from several vascular cell-types. In order to evaluate the possibility that Hcy may play a direct pro-inflammatory activity also in the joints of RA patients, we investigated: (i) the joint concentration of Hcy, and (ii) the effect of Hcy on cytokine production by unstimulated and IL-1beta-stimulated human RA cultured synoviocytes.


METHODS
In 5 RA and 5 controls subjects, Hcy was measured in the blood and knee synovial fluid, and specimens of synovial tissue were taken to obtain cell cultures. Cultures were incubated with Hcy (10-100 micromol/l) +/- IL-1beta, and IL-6 and IL-8 concentrations were evaluated in the supernatants (ELISA) together with the activation of nuclear factor-kB (NF-kB) (immunocytochemistry).


RESULTS
Hcy was present in synovial fluids, with a mean concentration significantly higher in RA patients than in controls (9.0 +/- 1.1 vs 5.9 +/- 1.2 micromol/l). Hcy enhanced IL-6 and IL-8 production in RA synoviocytes only (up to 35%). Moreover, Hcy produced a clear-cut activation of NF-kB in rheumatoid cells only.


CONCLUSIONS
Hcy enhances IL-1-dependent cytokine production by rheumatoid synoviocytes at a concentration measurable in RA joints in vivo. Thus, in RA patients, Hcy may not only represent an important risk factor for the progression of cardiovascular diseases, but it may also contribute to the joint damage.
Lazzerini
P E
PE
Department of Clinical Medicine and Immunological Sciences, Division of Clinical Immunology, University of Siena, Italy. pietroenea@yahoo.it
Selvi
E
E
Lorenzini
S
S
Capecchi
P L
PL
Ghittoni
R
R
Bisogno
S
S
Catenaccio
M
M
Marcolongo
R
R
Galeazzi
M
M
Laghi-Pasini
F
F
D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007719:Knee Joint; D016328:NF-kappa B / Q000378:metabolism; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism
D004338:Drug Combinations; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D006710:Homocysteine