Cyclosporin A inhibits CD69 expression induced on synovial fluid and peripheral blood lymphocytes by interleukin 15.
OBJECTIVE
To study the modulation of CD69 expression on peripheral blood (PB) and synovial fluid (SF) lymphocytes by interleukin 15 (IL-15) and several other cytokines and chemokines widely detected in the rheumatoid microenvironment. The effect of cyclosporin A (CSA) or methotrexate (MTX) in the cytokine mediated regulation of CD69 was analyzed.


METHODS
CD69 expression on lymphocytes was assessed by flow cytometry after incubation with different cytokines, chemokines, phorbol myristate acetate, or calcium ionophore in the presence or absence of CSA, MTX, or both. The effect of IL-15 and SF supernatants in maintaining CD69 expression on SF lymphocytes was also assessed. IL-15 levels in SF supernatants were measured by ELISA.


RESULTS
IL-15 induced the greatest upregulation of CD69 expression on PB lymphocytes in a time and dose dependent manner. IL-15 was able to maintain a high CD69 expression on SF lymphocytes. SF supernatants from rheumatoid arthritis (RA), which contain significant amounts of IL-15, also reversed the CD69 downregulation of SF lymphocytes in culture. CSA, but not MTX, inhibited the CD69 upregulation mediated by IL-15 both in PB and SF lymphocytes.


CONCLUSIONS
IL-15 appears to be responsible, at least in part, for the high CD69 expression on lymphocytes from the rheumatoid microenvironment. Consistent with the virtual absence of lymphocyte derived cytokines in RA synovium, the prevention of IL-15 mediated CD69 upregulation on lymphocytes may explain the effect of CSA in the treatment of RA.
Ortiz
A M
AM
Immunology Department, Hospital Universitario de la Princesa, Universidad Autónoma De Madrid, Spain.
García-Vicuña
R
R
Sancho
D
D
Laffon
A
A
Sánchez-Madrid
F
F
González-Alvaro
I
I
D015703:Antigens, CD / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018925:Chemokines / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019409:Interleukin-15 / Q000378:metabolism* / Q000494:pharmacology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018925:Chemokines; D016572:Cyclosporine; D016207:Cytokines; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D037181:Lectins, C-Type; D008727:Methotrexate; D000099192:CD69 Antigens