Cooperative induction of 15-lipoxygenase in rheumatoid synovial cells by IL-4 and proinflammatory cytokines.
OBJECTIVE
To clarify the role of interleukin-4 (IL-4) in the expression of 15-lipoxygenase (15-LOX), whose metabolities are known to suppress the inflammatory reaction, in freshly prepared rheumatoid synovial cells.


METHODS
Adherent synovial cells were prepared by enzymatic digestion of synovia obtained from patients with rheumatoid arthritis (RA). Protein expression of 15-LOX was determined by Western blot analysis. The messenger RNAs of 15-LOX were determined by reverse transcription and the polymerase chain reaction (RT-PCR).


RESULTS
Freshly prepared rheumatoid synovial cells did not express 15-LOX at either the mRNA or protein levels. IL-4 induced the protein expression of 15-LOX after 24 hours of culture. Although interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha), major inflammatory cytokines in rheumatoid synovia, did not induce the expression of 15-LOX, IL-4 and these inflammatory cytokines synergistically enhanced the protein expression of 15-LOX. The synergistic effect was also observed at the level of mRNA.


CONCLUSIONS
We demonstrate that IL-4 cooperated with the inflammatory cytokines IL-1 alpha and TNF alpha to enhance the expression of 15-LOX in rheumatoid synovial cells. Since 15-LOX metabolites have potent anti-inflammatory actions, our data suggest that IL-4 might downregulate rheumatoid inflammation via the induction of 15-LOX and its metabolites.
Harada
S
S
First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Sugiyama
E
E
Takebe
S
S
Taki
H
H
Shinoda
K
K
Mohamed
S G
SG
Maruyama
M
M
Hamazaki
T
T
Kobayashi
M
M
D000527:Alprostadil / Q000032:analysis / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000187:drug effects / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000503:physiopathology; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D001093:Arachidonate 15-Lipoxygenase; D000527:Alprostadil