Interleukin 17, a nitric oxide-producing cytokine with a peroxynitrite-independent inhibitory effect on proteoglycan synthesis.
OBJECTIVE
To compare the potency of 2 cytokines, interleukin 17 (IL-17) and IL-1beta, on rat cartilage proteoglycan synthesis with special attention to nitric oxide (NO) and peroxynitrite formation.


METHODS
Chondrocytes in alginate beads were stimulated with human recombinant (rh) IL-17 (0.03 to 300.0 ng/ml) and/or rhIL-1beta (0.25 to 25.0 ng/ml) in the presence or not of L-NMMA or CuDips. Alternatively, rats were injected with either IL-17 (10.0 micro g) or IL-1beta (1.0 micro g) into each knee joint. NO concentrations were determined by a spectrofluorimetric assay, proteoglycan synthesis by 35SO4-2 incorporation, peroxynitrite generation by immunostaining for 3-nitrotyrosine, and IL-1beta mRNA expression by reverse transcription-polymerase chain reaction.


RESULTS
IL-17 inhibited proteoglycan synthesis and increased NO production, both in vitro and in vivo, without inducing expression of IL-1beta mRNA in cartilage. Additive effects were observed when IL-17 was combined with low concentrations of IL-1. Surprisingly, a similar NO synthesis between IL-1 and IL-17 led to a less suppressive effect of IL-17 on cartilage anabolism than with IL-1. Both in vitro and in vivo, peroxynitrite formation was extensive with IL-1beta, but negligible or nonexistent with IL-17. L-NMMA and CuDips completely corrected the suppressive effect of IL-1beta on proteoglycan synthesis, unlike with IL-17.


CONCLUSIONS
These data showed that NO is weakly involved in the IL-17 mediated inhibition of proteoglycan synthesis in rat. NO overload may not be predictive of any inhibitory effect on cartilage anabolism, but instead superoxide is a key regulator of NO contribution to chondrocyte dysfunction. Since IL-17 is a NO-producing cytokine with additive effects when combined with IL-1, it may play a pivotal role in cartilage destruction during rheumatoid arthritis, for which infiltrating cells produce high levels of superoxide and proinflammatory cytokines.
Pacquelet
Sandrine
S
Faculté de Médecine, Vandoeuvre-lès-Nancy, France.
Presle
Nathalie
N
Boileau
Christelle
C
Dumond
Hélène
H
Netter
Patrick
P
Martel-Pelletier
Johanne
J
Pelletier
Jean-Pierre
JP
Terlain
Bernard
B
Jouzeau
Jean-Yves
JY
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006614:Hindlimb / Q000187:drug effects; D007270:Injections, Intra-Articular; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology*; D007596:Joints / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D011509:Proteoglycans / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology
D004338:Drug Combinations; D007375:Interleukin-1; D020381:Interleukin-17; D011509:Proteoglycans; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012459:Salicylates; D030421:Peroxynitrous Acid; C030865:copper bis(3,5-diisopropylsalicylate); D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester