The response of T cells to interleukin-6 is differentially regulated by the microenvironment of the rheumatoid synovial fluid and tissue.
OBJECTIVE
Interleukin-6 (IL-6) is a proinflammatory cytokine with regulatory effects on the survival and differentiation of T cells. It exerts its biologic function in 2 ways: by directly binding to the IL-6 receptor (IL-6R; CD126) or via trans-signaling, in which soluble IL-6R/IL-6 complexes bind to the signaling component CD130. This study was undertaken to assess the expression and regulation of CD126 and CD130 and determine how these affect the response of CD4+ T cells to IL-6 in the joints of patients with rheumatoid arthritis (RA).


METHODS
Flow cytometry and immunofluorescence microscopy were used to determine the expression, function, and regulation of CD126 and CD130 in CD4+ T cells from the peripheral blood (PB), synovial fluid (SF), and synovial tissue of RA patients.


RESULTS
Compared to the findings in RA PB, CD4+ T cells in the SF and synovial tissue expressed low levels of CD126. In contrast, whereas CD4+ T cell expression of CD130 was minimal in the SF, its level in the synovial tissue was high. Consistent with this phenotype, synovial tissue T cells responded to trans-signaling by soluble IL-6R/IL-6 complexes, whereas no response was evident in CD4+ T cells from the SF. Down-regulation of both receptor components in SF T cells could be explained by exposure to high levels of IL-6. Increased levels of CD130 messenger RNA and protein in synovial tissue CD4+ T cells suggested that CD130 is up-regulated locally. Among a range of cytokines tested, only IL-10 induced CD130 expression in T cells.


CONCLUSIONS
The inflamed microenvironment in the synovial tissue maintains responsiveness to IL-6 trans-signaling through the up-regulation of CD130 expression in CD4+ T cells, and this process may be driven by IL-10.
University of Birmingham, Birmingham, UK.
Ester
E
Hidalgo
Sarah J
SJ
Essex
Lorraine
L
Yeo
S John
SJ
Curnow
Andrew
A
Filer
Mark S
MS
Cooper
Andrew M
AM
Thomas
Helen M
HM
McGettrick
Michael
M
Salmon
Christopher D
CD
Buckley
Karim
K
Raza
Dagmar
D
Scheel-Toellner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053698:Interleukin-6 Receptor alpha Subunit / Q000378:metabolism; D007596:Joints / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013582:Synovial Fluid / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology
D015850:Interleukin-6; D053698:Interleukin-6 Receptor alpha Subunit; D050822:Cytokine Receptor gp130