Enhanced tryptophan degradation in systemic lupus erythematosus.
In vitro and in vivo, tryptophan degradation was found to be associated with T cell functional loss and tolerance induction. In systemic lupus erythematosus (SLE) besides the Th2-type cytokine interleukin-10, Th1-type cytokines including interferon-gamma (IFN-gamma) are expressed especially during exacerbation of the disease. IFN-gamma stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) converting tryptophan to the metabolite kynurenine which in macrophages is subsequently degraded to other, partly neurotoxic compounds like quinolinic acid, and finally to nicrotinamides. We measured kynurenine and tryptophan concentrations in the sera of 55 SLE patients. In these patients, the concentrations of tryptophan (median, interquartile range: 53.9, 45.7-64.1 microM) were lower (p < 0.0001), and the kynurenine concentrations (2.45, 1.75-3.40 microM) were increased (p < 0.0005) compared to healthy blood donors (70.0, 63.8-80.6; 1.80, 1.45-2.27 microM, respectively). Also the kynurenine per tryptophan quotients (K/T), which allow to estimate IDO activity, were significantly higher in patients than in normals (0.043, 0.033-0.062 vs. 0.027, 0.021-0.030; p < 0.0001), indicating enhanced IDO-induced tryptophan degradation in SLE. There was no significant relationship between tryptophan, kynurenine and the SLEDAI, and also the correlation of K/T with SLEDAI was rather weak (rs = 0.243, p < 0.05). Higher K/T was found in patients presenting with serositis (p = 0.01), decrease of complement (c3, c4; p < 0.01) and blood count change (anemia, leucopenia, lymphopenia; p = 0.032) than in patients without such disease manifestations. The significant correlation found between K/T and neopterin (rs = 0.808, p < 0.001), a marker of immune activation, points to a role of immune activation to be responsible for tryptophan degradation in SLE patients.
Widner
B
B
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Sepp
N
N
Kowald
E
E
Ortner
U
U
Wirleitner
B
B
Fritsch
P
P
Baier-Bitterlich
G
G
Fuchs
D
D
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007737:Kynurenine / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood; D014364:Tryptophan / Q000097:blood / Q000378:metabolism*
D007737:Kynurenine; D019798:Neopterin; D014364:Tryptophan