Amplification of the synovial inflammatory response through activation of MAPK and NF- kappaB

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Arthritis Rheum. 2004 Jul;50(7):2167-77.

Amplification of the synovial inflammatory response through activation

of mitogen-activated protein kinases and nuclear factor kappaB using

ligation of CD40 on CD14+ synovial cells from patients with rheumatoid

arthritis.

Harigai M, Hara M, Kawamoto M, Kawaguchi Y, Sugiura T, Tanaka M,

Nakagawa M, Ichida H, Takagi K, Higami-Ohsako S, Shimada K, Kamatani N.

Institute of Rheumatology, Tokyo Women's Medical University, Tokyo,

Japan.

OBJECTIVE: To determine the signal transduction pathways in CD14+

synovial cells from patients with rheumatoid arthritis (RA) after CD40

ligation, and to examine their role in amplifying synovial inflammation

in affected joints. METHODS: Expression of messenger RNA was analyzed

using quantitative reverse transcription-polymerase chain reaction.

Cytokines and chemokines were measured using enzyme-linked immunosorbent

assay. Activation of kinases was detected using Western blotting.

Nuclear translocation of NF-kappaB was examined using

immunohistochemistry. CD14+ synovial cells were enriched using magnetic

cell sorting. Fibroblast-like synoviocytes (FLS) were obtained by

passaging primary synovial cell culture. RESULTS: Stimulation of CD14+

synovial cells from RA patients by recombinant soluble CD154 (rsCD154)

significantly induced expression of tumor necrosis factor alpha

(TNFalpha), interleukin-1alpha (IL-1alpha), and IL-1beta. CD14+ RA

synovial cells stimulated with rsCD154 plus interferon-gamma (IFNgamma)

induced significantly higher production of IL-6, IL-8, and monocyte

chemoattractant protein 1 by FLS compared with unstimulated CD14+

synovial cells, through TNFalpha-, IL-1alpha-, and IL-1beta-mediated

pathways. Stimulation with rsCD154 plus IFNgamma induced the activation

of ERK-1/2, p38 MAPK, and NF-kappaB. Specific inhibitors of MAPK/ERK-1/2

kinases and p38 MAPK significantly reduced the production of TNFalpha

and IL-1beta by rsCD154 plus IFNgamma-stimulated CD14+ synovial cells,

and also inhibited production of these cytokines by freshly isolated

synovial cells from RA patients.

CONCLUSION: These data indicate that the CD40-CD154 interaction

activates the ERK, p38, and NF-kappaB pathways in CD14+ synovial cells

from RA patients to produce TNFalpha, IL-1alpha, and IL-1beta, which in

turn amplifies inflammatory responses by stimulating FLS. Inhibition of

the CD40-CD154 interaction or its signal transduction pathways would be

a strong and efficient strategy for the management of synovial

inflammation in RA.

PMID: 15248214

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