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Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK).
Arthritis Rheum. 1999 Nov; 42(11):2399-409.AR

Abstract

OBJECTIVE

To explore the signaling pathways by which the proinflammatory cytokine interleukin-17 (IL-17) may contribute to cartilage catabolism in osteoarthritis (OA) by inducing inducible nitric oxide synthase (iNOS) expression in chondrocytes.

METHODS

We examined the IL-17-induced NO production in human OA chondrocytes, in combination with the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha (TNF alpha), and leukemia inhibitory factor (LIF); the antiinflammatory cytokines IL-4, IL-10, and IL-13; and IL-1 receptor antagonist (IL-1Ra). Further, we explored the major intracellular signaling pathways through which IL-17 induced iNOS expression and NO production.

RESULTS

Treatment with IL-17 induced a dose-dependent increase in the level of NO. When IL-17 was combined with the above factors, it resulted in a synergistic effect with TNF alpha, an additive effect with LIF, and no further effect than when used alone with IL-1beta. IL-4, IL-10, IL-13, and IL-1Ra had no true effect on IL-17-induced NO production. The cAMP mimetics, 3-isobutyl-1-methyl xanthine plus forskolin, completely blocked IL-17-induced NO production. KT-5720, genistein, and Calphostin C, inhibitors of protein kinase A (PKA), tyrosine kinase, and protein kinase C, respectively, reduced the IL-17-induced NO production by 72%, 56%, and 42%, respectively. Within minutes, IL-17 induced the phosphorylation of mitogen-activated protein kinase kinase-1/2 (MEK-1/2), -3/6 (MKK-3/6), p44/42, p38, and inhibitor of nuclear factor kappaB (I kappaB)-alpha, as well as the activation of mitogen-activated protein kinase-activated protein kinase-1 and -2 (MAPKAPK-1 and -2). Interestingly, IL-17 induced phosphorylation of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) (p54/46) only when PKA was inhibited. Specific protein kinase inhibitors for MEK-1/2 (PD98059), p38 (SB202190), and nuclear factor kappaB (NF-kappaB) (pyrrolidine dithiocarbamate) each markedly decreased the IL-17-increased iNOS level and NO production. Inhibiting MAPK, including MEK-1/2 and p38, had no effect on the IL-17-induced activation of IkappaB-alpha, but reversed the IL-17 activation of MAPKAPK-1 and -2, respectively.

CONCLUSION

These findings show that the stimulation of NO production by IL-17 is mediated mainly by a complex activation of kinases, especially PKA, NF-kappaB, and MAPK. NF-kappaB appears to require MAPK activation, with downstream activation of MAPKAPK probably acting as a transactivating factor, to induce iNOS expression.

Authors+Show Affiliations

Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10555036

Citation

Martel-Pelletier, J, et al. "Mitogen-activated Protein Kinase and Nuclear Factor kappaB Together Regulate Interleukin-17-induced Nitric Oxide Production in Human Osteoarthritic Chondrocytes: Possible Role of Transactivating Factor Mitogen-activated Protein Kinase-activated Proten Kinase (MAPKAPK)." Arthritis and Rheumatism, vol. 42, no. 11, 1999, pp. 2399-409.
Martel-Pelletier J, Mineau F, Jovanovic D, et al. Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK). Arthritis Rheum. 1999;42(11):2399-409.
Martel-Pelletier, J., Mineau, F., Jovanovic, D., Di Battista, J. A., & Pelletier, J. P. (1999). Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK). Arthritis and Rheumatism, 42(11), 2399-409.
Martel-Pelletier J, et al. Mitogen-activated Protein Kinase and Nuclear Factor kappaB Together Regulate Interleukin-17-induced Nitric Oxide Production in Human Osteoarthritic Chondrocytes: Possible Role of Transactivating Factor Mitogen-activated Protein Kinase-activated Proten Kinase (MAPKAPK). Arthritis Rheum. 1999;42(11):2399-409. PubMed PMID: 10555036.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK). AU - Martel-Pelletier,J, AU - Mineau,F, AU - Jovanovic,D, AU - Di Battista,J A, AU - Pelletier,J P, PY - 1999/11/11/pubmed PY - 1999/11/11/medline PY - 1999/11/11/entrez SP - 2399 EP - 409 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 42 IS - 11 N2 - OBJECTIVE: To explore the signaling pathways by which the proinflammatory cytokine interleukin-17 (IL-17) may contribute to cartilage catabolism in osteoarthritis (OA) by inducing inducible nitric oxide synthase (iNOS) expression in chondrocytes. METHODS: We examined the IL-17-induced NO production in human OA chondrocytes, in combination with the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha (TNF alpha), and leukemia inhibitory factor (LIF); the antiinflammatory cytokines IL-4, IL-10, and IL-13; and IL-1 receptor antagonist (IL-1Ra). Further, we explored the major intracellular signaling pathways through which IL-17 induced iNOS expression and NO production. RESULTS: Treatment with IL-17 induced a dose-dependent increase in the level of NO. When IL-17 was combined with the above factors, it resulted in a synergistic effect with TNF alpha, an additive effect with LIF, and no further effect than when used alone with IL-1beta. IL-4, IL-10, IL-13, and IL-1Ra had no true effect on IL-17-induced NO production. The cAMP mimetics, 3-isobutyl-1-methyl xanthine plus forskolin, completely blocked IL-17-induced NO production. KT-5720, genistein, and Calphostin C, inhibitors of protein kinase A (PKA), tyrosine kinase, and protein kinase C, respectively, reduced the IL-17-induced NO production by 72%, 56%, and 42%, respectively. Within minutes, IL-17 induced the phosphorylation of mitogen-activated protein kinase kinase-1/2 (MEK-1/2), -3/6 (MKK-3/6), p44/42, p38, and inhibitor of nuclear factor kappaB (I kappaB)-alpha, as well as the activation of mitogen-activated protein kinase-activated protein kinase-1 and -2 (MAPKAPK-1 and -2). Interestingly, IL-17 induced phosphorylation of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) (p54/46) only when PKA was inhibited. Specific protein kinase inhibitors for MEK-1/2 (PD98059), p38 (SB202190), and nuclear factor kappaB (NF-kappaB) (pyrrolidine dithiocarbamate) each markedly decreased the IL-17-increased iNOS level and NO production. Inhibiting MAPK, including MEK-1/2 and p38, had no effect on the IL-17-induced activation of IkappaB-alpha, but reversed the IL-17 activation of MAPKAPK-1 and -2, respectively. CONCLUSION: These findings show that the stimulation of NO production by IL-17 is mediated mainly by a complex activation of kinases, especially PKA, NF-kappaB, and MAPK. NF-kappaB appears to require MAPK activation, with downstream activation of MAPKAPK probably acting as a transactivating factor, to induce iNOS expression. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/10555036/Mitogen_activated_protein_kinase_and_nuclear_factor_kappaB_together_regulate_interleukin_17_induced_nitric_oxide_production_in_human_osteoarthritic_chondrocytes:_possible_role_of_transactivating_factor_mitogen_activated_protein_kinase_activated_proten_kinase__MAPKAPK__ L2 - https://doi.org/10.1002/1529-0131(199911)42:11<2399::AID-ANR19>3.0.CO;2-Y DB - PRIME DP - Unbound Medicine ER -