Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: A mechanism for methotrexate-induced nodulosis in rheumatoid arthritis

Objective To examine the potential of methotrexate (MTX) to acts as a differentiation‐stimulating factor for monocytes, which could explain the antiinflammatory properties of this agent in the treatment of rheumatoid arthritis (RA). Methods Fluorescence‐activated cell sorter analysis was used to measure the changes in antigen expression (CD11b/c, CD16, CD64, CD14, CD68, and CD95) in response to MTX, 1,25‐OH‐cholecalciferol (1,25‐OH‐CCF), and granulocyte‐macrophage colony‐stimulating factor in the human monoblastic leukemia cell line U937, bone marrow mononuclear cells (BMMC), and peripheral blood mononuclear cells (PBMC). Release of interleukin‐1β (IL‐1β), IL‐1 receptor antagonist (IL‐1Ra), tumor necrosis factor α, and soluble tumor necrosis factor receptors (sTNFR) p55 and p75 during the differentiation in vitro was assessed by immunoassay in the culture supernatants. Results MTX alone and in combination with 1,25‐OH‐CCF markedly stimulated the differentiation of the monocytic U937 cells and simultaneously increased Fas‐antigen expression. Differentiation was associated with enhanced IL‐1Ra and sTNFR p75 release from U937 cells. MTX had fewer effects on phenotypic differentiation of human BMMC and PBMC, but did stimulate IL‐1Ra release and inhibit IL‐1β synthesis in BMMC. Conclusion MTX acts as a strong differentiation factor for immature and undifferentiated monocytic cells. Differentiation in vitro is associated with an increase in natural cytokine inhibitor release and a simultaneous down‐regulation of IL‐1β. These findings may explain the marked clinical antiinflammatory effects of MTX when used in the treatment of RA.

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Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes

Seitz

Zwicker

Loetscher

1998

Arthritis & Rheumatism

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Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes

Weyand¹,

Klimiuk²,

Goronzy³

1998

Springer Semin Immunopathol

114

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Rheumatoid arthritis (RA) is now recognized as a multigene disorder with a number of genetic polymorphisms contributing to disease pathogenesis. Here, we propose that the diagnostic category of RA includes multiple subtypes of disease and that the different phenotypes of RA correlate to different genotypes. Support for this concept has come from a reappraisal of the clinical heterogeneity of RA and the observation that HLA-DRB1 polymorphisms are useful in describing genetic heterogeneity of RA phenotypes. A series of HLA-DRB1 genes has been identified as RA associated, and in recent years emphasis has been put on the sequence similarities of these alleles. An alternative view focuses on the amino acid variations found in RA-associated HLA-DRB1 alleles with different alleles being enriched in distinct subtypes of RA. Rheumatoid factor-positive destructive joint disease is predominantly associated with the HLA-DRB1*0401 allele, while HLA-DRB1*0404 and B1*0101 predispose for milder and often seronegative disease. Expression of disease-associated alleles on both haplotypes carries a high risk for extra-articular manifestations. In particular, patients homozygous for HLA-DRB1*0401 frequently develop rheumatoid vasculities on follow-up. Besides HLA gene polymorphisms, abnormalities in the generation and function of CD4 T cells and in inflammatory pathways established in synovial lesions can be used to dissect patient subsets with different variants of RA. Emergence of CD28-deficient CD4 T cells identifies RA patients with extra-articular manifestations. These cells undergo clonal expansion in vivo, produce high amounts of IFN-gamma, and exhibit autoreactivity. Concordance of monozygotic twins for the expression of CD4+ CD28- T cells suggests a role for genetic factors in the generation of these unusual T cells. Evidence for heterogeneity of the synovial component of RA comes from studies describing three distinct patterns of lymphoid organization in the synovium. Based upon the topography of tissue-infiltrating mononuclear cells, diffuse, follicular, and granulomatous variants of rheumatoid synovitis can be distinguished. Each pattern of lymphoid organization correlates with a unique profile of tissue cytokines, demonstrating that several pathways of immune deviation modulate disease expression in RA. A dissection of RA variants would have major implications on how the disease is studied, treated, and managed. Identifying combinations of RA risk genes that correlate with disease variants could, therefore, become an important diagnostic tool.

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The role of adenosine A1 receptor on immune cells

2022

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Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: A mechanism for methotrexate-induced nodulosis in rheumatoid arthritis

Abstract: Agents that inhibit adenosine A1 receptors might be useful in the treatment of MTX-induced rheumatoid nodulosis, while still potentiating the A2-mediated antiinflammatory effects of MTX on synovitis.

Cited by 77 publications

References 28 publications

Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes

Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes

Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes

The role of adenosine A1 receptor on immune cells

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