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Expression of mitogen-activated protein kinase phosphatase 1, a negative regulator of the mitogen-activated protein kinases, in rheumatoid arthritis: up-regulation by interleukin-1beta and glucocorticoids.
Arthritis Rheum. 2004 Oct; 50(10):3118-28.AR

Abstract

OBJECTIVE

Mitogen-activated protein kinases (MAPKs) are activated by proinflammatory stimuli. MAPK phosphatases (MKPs), in particular MKP-1, have been identified as endogenous negative regulators of MAPK activation. Since MAPKs are known to be important in rheumatoid arthritis (RA) synoviocyte activation, this study assessed the expression, regulation, and function of MKP-1 in RA.

METHODS

MKP-1 expression was measured by Western blotting (WB) and real-time polymerase chain reaction (PCR). RA fibroblast-like synoviocytes (FLS) were treated with interleukin-1beta (IL-1beta), tumor necrosis factor alpha, fetal calf serum, and dexamethasone. Expression of MAPKs in RA FLS was analyzed by WB using phosphospecific antibodies, while IL-6 expression was assessed by real-time PCR.

RESULTS

MKP-1 protein and messenger RNA were detected in cultured RA FLS. IL-1beta rapidly up-regulated MKP-1, coinciding with reciprocal down-regulation of ERK, JNK, and p38 MAPK phosphorylation. Dexamethasone rapidly and sustainably up-regulated MKP-1, and this also coincided with down-regulation of ERK, JNK, and p38 MAPK phosphorylation. In addition, dexamethasone augmented IL-1beta-induced up-regulation of MKP-1, and this was associated with inhibition of ERK, JNK, and p38 MAPK phosphorylation and IL-6 expression. Dexamethasone had no effect on the phosphorylation of upstream kinases such as MEKK-3/6. In the presence of glucocorticoid (GC) receptor antagonist RU 486, the dexamethasone-mediated up-regulation of MKP-1 was impaired. Moreover, inhibition of MKP-1 expression impaired dexamethasone-mediated inhibition of MAPK phosphorylation.

CONCLUSION

This study demonstrates the expression of MKP-1 in RA FLS. Cytokine and GC regulation of MKP-1 may be important in determining the magnitude of the inflammatory response in RA that is mediated via MAPKs. The effects of GCs in RA may be mediated, in part, via GC receptor-dependent up-regulation of MKP-1.

Authors+Show Affiliations

Monash Medical Centre, Clayton, Melbourne, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15476200

Citation

Toh, Myew-Ling, et al. "Expression of Mitogen-activated Protein Kinase Phosphatase 1, a Negative Regulator of the Mitogen-activated Protein Kinases, in Rheumatoid Arthritis: Up-regulation By Interleukin-1beta and Glucocorticoids." Arthritis and Rheumatism, vol. 50, no. 10, 2004, pp. 3118-28.
Toh ML, Yang Y, Leech M, et al. Expression of mitogen-activated protein kinase phosphatase 1, a negative regulator of the mitogen-activated protein kinases, in rheumatoid arthritis: up-regulation by interleukin-1beta and glucocorticoids. Arthritis Rheum. 2004;50(10):3118-28.
Toh, M. L., Yang, Y., Leech, M., Santos, L., & Morand, E. F. (2004). Expression of mitogen-activated protein kinase phosphatase 1, a negative regulator of the mitogen-activated protein kinases, in rheumatoid arthritis: up-regulation by interleukin-1beta and glucocorticoids. Arthritis and Rheumatism, 50(10), 3118-28.
Toh ML, et al. Expression of Mitogen-activated Protein Kinase Phosphatase 1, a Negative Regulator of the Mitogen-activated Protein Kinases, in Rheumatoid Arthritis: Up-regulation By Interleukin-1beta and Glucocorticoids. Arthritis Rheum. 2004;50(10):3118-28. PubMed PMID: 15476200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of mitogen-activated protein kinase phosphatase 1, a negative regulator of the mitogen-activated protein kinases, in rheumatoid arthritis: up-regulation by interleukin-1beta and glucocorticoids. AU - Toh,Myew-Ling, AU - Yang,Yuan, AU - Leech,Michelle, AU - Santos,Lanie, AU - Morand,Eric F, PY - 2004/10/12/pubmed PY - 2004/12/16/medline PY - 2004/10/12/entrez SP - 3118 EP - 28 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 50 IS - 10 N2 - OBJECTIVE: Mitogen-activated protein kinases (MAPKs) are activated by proinflammatory stimuli. MAPK phosphatases (MKPs), in particular MKP-1, have been identified as endogenous negative regulators of MAPK activation. Since MAPKs are known to be important in rheumatoid arthritis (RA) synoviocyte activation, this study assessed the expression, regulation, and function of MKP-1 in RA. METHODS: MKP-1 expression was measured by Western blotting (WB) and real-time polymerase chain reaction (PCR). RA fibroblast-like synoviocytes (FLS) were treated with interleukin-1beta (IL-1beta), tumor necrosis factor alpha, fetal calf serum, and dexamethasone. Expression of MAPKs in RA FLS was analyzed by WB using phosphospecific antibodies, while IL-6 expression was assessed by real-time PCR. RESULTS: MKP-1 protein and messenger RNA were detected in cultured RA FLS. IL-1beta rapidly up-regulated MKP-1, coinciding with reciprocal down-regulation of ERK, JNK, and p38 MAPK phosphorylation. Dexamethasone rapidly and sustainably up-regulated MKP-1, and this also coincided with down-regulation of ERK, JNK, and p38 MAPK phosphorylation. In addition, dexamethasone augmented IL-1beta-induced up-regulation of MKP-1, and this was associated with inhibition of ERK, JNK, and p38 MAPK phosphorylation and IL-6 expression. Dexamethasone had no effect on the phosphorylation of upstream kinases such as MEKK-3/6. In the presence of glucocorticoid (GC) receptor antagonist RU 486, the dexamethasone-mediated up-regulation of MKP-1 was impaired. Moreover, inhibition of MKP-1 expression impaired dexamethasone-mediated inhibition of MAPK phosphorylation. CONCLUSION: This study demonstrates the expression of MKP-1 in RA FLS. Cytokine and GC regulation of MKP-1 may be important in determining the magnitude of the inflammatory response in RA that is mediated via MAPKs. The effects of GCs in RA may be mediated, in part, via GC receptor-dependent up-regulation of MKP-1. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/15476200/Expression_of_mitogen_activated_protein_kinase_phosphatase_1_a_negative_regulator_of_the_mitogen_activated_protein_kinases_in_rheumatoid_arthritis:_up_regulation_by_interleukin_1beta_and_glucocorticoids_ L2 - https://doi.org/10.1002/art.20580 DB - PRIME DP - Unbound Medicine ER -