RESEARCH - MTX specifically modulates cytokine production by T cells and macrophages

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Clin Exp Immunol. 1999 Jan;115(1):42-55.

Methotrexate specifically modulates cytokine production by T cells and

macrophages in murine collagen-induced arthritis (CIA): a mechanism for

methotrexate-mediated immunosuppression.

Neurath MF, Hildner K, Becker C, Schlaak JF, Barbulescu K, Germann T,

Schmitt E, Schirmacher P, Haralambous S, Pasparakis M, Meyer Zum

Buschenfelde KH, Kollias G, Marker-Hermann E.

Laboratory of Immunology, I Medical Clinic, University of Mainz, Germany.

Immunosuppressive therapy with methotrexate (MTX) has been established as

effective treatment for patients with rheumatoid arthritis. To analyse the

therapeutic potential and mechanisms of action of MTX, we determined serum

cytokine levels and cytokine production by splenic T cells and macrophages

in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX

in a murine model of experimental arthritis induced by collagen type II

(CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor

(TNF) production by splenic T cells but not by macrophages from healthy mice

in vitro in a dose-dependent manner. In contrast, interferon-gamma

(IFN-gamma) production was less strikingly reduced and IL-4 production was

virtually unaffected. In addition, treatment of healthy mice with MTX in

vivo led to reduced TNF serum levels and diminished TNF production by

splenic T cells and macrophages. Intraperitoneal administration of MTX prior

to the onset of arthritis completely prevented clinical and pathological

signs of CIA. This was associated with a striking reduction of TNF

production by spleen cells from MTX-treated mice. The role of TNF in

MTX-mediated effects on cytokine production was further underlined by the

finding that MTX effects on IFN-gamma production were augmented in

TNF-transgenic mice but abrogated in mice in which the TNF-alpha gene had

been inactivated by homologous recombination. Thus, MTX specifically

modulates spontaneous and IL-15-induced TNF-alpha production in mice and

prevents experimental murine CIA. These data suggest that TNF production by

T cells is an important target of MTX and may serve as a basis to understand

and further analyse MTX-mediated mechanisms of immunosuppression in patients

with RA.

PMID: 9933419

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=9\

933419 & dopt=Abstract

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