Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells

Journal Article · Fri Mar 15 04:00:00 EST 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.6.2441· OSTI ID:5030276

Cronstein, B N; Eberle, M A; Levin, R I ^[1]; Gruber, H E ^[2]

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1. New York Univ. Medical Center, New York (United States)
2. Gensia Pharmaceuticals, Inc., San Diego, CA (United States)

Although commonly used to control a variety of inflammatory diseases, the mechanism of action of a low dose of methotrexate remains a mystery. Methotrexate accumulates intracellularly where it may interfere with purine metabolism. Therefore, the authors determined whether a 48-hr pretreatment with methotrexate affected adenosine release from ({sup 14}C)adenine-labeled human fibroblasts and umbilical vein endothelial cells. Methotrexate significantly increased adenosine release by fibroblasts. The effect of methotrexate on adenosine release was not due to cytotoxicity since cells treated with maximal concentrations of methotrexate took up ({sup 14}C)adenine and released {sup 14}C-labeled purine (a measure of cell injury) in a manner identical to control cells. Methotrexate treatment of fibroblasts dramatically inhibited adherence to fibroblasts by both unstimulated neutrophils and stimulated neutrophils. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, methotrexate induces the accumulation of AICAR, the nucleoside precursor of which has previously been shown to cause adenosine release from ischemic cardiac tissue. The observation that the antiinflammatory actions of methotrexate are due to the capacity of methotrexate to induce adenosine release may form the basis for the development of an additional class of antiinflammatory drugs.

• OSTI ID: 5030276
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 88:6; ISSN PNASA; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ADENOSINE
ANIMAL CELLS
ANIMAL TISSUES
ANTIMETABOLITES
AROMATICS
AZAARENES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
CARBON 14 COMPOUNDS
CARBON COMPOUNDS
CELL CULTURES
CONNECTIVE TISSUE CELLS
DRUGS
ENDOTHELIUM
FIBROBLASTS
HETEROCYCLIC COMPOUNDS
INFLAMMATION
LABELLED COMPOUNDS
LEUKOCYTES
MATERIALS
METABOLISM
METHOTREXATE
NEUTROPHILS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PATHOLOGICAL CHANGES
PHARMACOLOGY
PURINES
RIBOSIDES
SOMATIC CELLS
SYMPTOMS
TISSUES