Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor α production by rheumatoid synoviocytes

Mi La Cho, Wan Uk Kim, So Youn Min, Do June Min, Jun Ki Min, Sang Heon Lee, Sung Hwan Park, Chul Soo Cho, Ho Youn Kim

Research output: Contribution to journalArticle

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Abstract

Objective. To determine the direct effect of cyclosporin A (CSA) on the production of cytokines by rheumatoid synovial fibroblasts. Methods. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis and cultured in the presence of CSA. The production of interleukin-10 (IL-10), IL-15, and tumor necrosis factor α (TNFα) by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The expression of IL-10, IL-15, and TNFα messenger RNA (mRNA) in FLS was determined by polymerase chain reaction (PCR). Results. CSA (1-1,000 ng/ml) increased the production of IL-10, but decreased in a dose-dependent manner the levels of IL-15 and TNFα that were spontaneously secreted from FLS. CSA also potently inhibited the production of IL-15 and TNFα stimulated with interferon-γ, IL-1β, or lipopolysaccharide. The inhibitory effect of CSA on IL-15 and TNFα production depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. In a semiquantitative PCR, CSA increased IL-10 mRNA expression but strongly suppressed IL-1β-induced IL-15 and TNFα mRNA expression, indicating that the production of these cytokines by CSA was regulated at the transcriptional level. Results with the calcineurin inhibitor FK-506, but not with the immunosuppressant rapamycin, were similar to those with CSA. Agonists of cAMP displayed an additive effect on the changes produced in the IL-10, IL-15, and TNFα levels by CSA, while a cAMP antagonist almost completely abrogated the effect of CSA, suggesting that cAMP is the major intracellular signal that mediates cytokine regulation by CSA. Conclusion. These results suggest that CSA differentially regulates the production of cytokines by rheumatoid synoviocytes via a cAMP-dependent pathway.

Original languageEnglish (US)
Pages (from-to)42-51
Number of pages10
JournalArthritis and Rheumatism
Volume46
Issue number1
DOIs
StatePublished - 2002

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Interleukin-15
Interleukin-10
Cyclosporine
Tumor Necrosis Factor-alpha
Fibroblasts
Cytokines
Interleukin-1
Messenger RNA
Synoviocytes
Polymerase Chain Reaction
Tacrolimus
Sirolimus
Immunosuppressive Agents
Interferons
Lipopolysaccharides
Rheumatoid Arthritis

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor α production by rheumatoid synoviocytes. / Cho, Mi La; Kim, Wan Uk; Min, So Youn; Min, Do June; Min, Jun Ki; Lee, Sang Heon; Park, Sung Hwan; Cho, Chul Soo; Kim, Ho Youn.

In: Arthritis and Rheumatism, Vol. 46, No. 1, 2002, p. 42-51.

Research output: Contribution to journalArticle

Cho, Mi La ; Kim, Wan Uk ; Min, So Youn ; Min, Do June ; Min, Jun Ki ; Lee, Sang Heon ; Park, Sung Hwan ; Cho, Chul Soo ; Kim, Ho Youn. / Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor α production by rheumatoid synoviocytes. In: Arthritis and Rheumatism. 2002 ; Vol. 46, No. 1. pp. 42-51.
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abstract = "Objective. To determine the direct effect of cyclosporin A (CSA) on the production of cytokines by rheumatoid synovial fibroblasts. Methods. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis and cultured in the presence of CSA. The production of interleukin-10 (IL-10), IL-15, and tumor necrosis factor α (TNFα) by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The expression of IL-10, IL-15, and TNFα messenger RNA (mRNA) in FLS was determined by polymerase chain reaction (PCR). Results. CSA (1-1,000 ng/ml) increased the production of IL-10, but decreased in a dose-dependent manner the levels of IL-15 and TNFα that were spontaneously secreted from FLS. CSA also potently inhibited the production of IL-15 and TNFα stimulated with interferon-γ, IL-1β, or lipopolysaccharide. The inhibitory effect of CSA on IL-15 and TNFα production depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. In a semiquantitative PCR, CSA increased IL-10 mRNA expression but strongly suppressed IL-1β-induced IL-15 and TNFα mRNA expression, indicating that the production of these cytokines by CSA was regulated at the transcriptional level. Results with the calcineurin inhibitor FK-506, but not with the immunosuppressant rapamycin, were similar to those with CSA. Agonists of cAMP displayed an additive effect on the changes produced in the IL-10, IL-15, and TNFα levels by CSA, while a cAMP antagonist almost completely abrogated the effect of CSA, suggesting that cAMP is the major intracellular signal that mediates cytokine regulation by CSA. Conclusion. These results suggest that CSA differentially regulates the production of cytokines by rheumatoid synoviocytes via a cAMP-dependent pathway.",
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T1 - Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor α production by rheumatoid synoviocytes

AU - Cho, Mi La

AU - Kim, Wan Uk

AU - Min, So Youn

AU - Min, Do June

AU - Min, Jun Ki

AU - Lee, Sang Heon

AU - Park, Sung Hwan

AU - Cho, Chul Soo

AU - Kim, Ho Youn

PY - 2002

Y1 - 2002

N2 - Objective. To determine the direct effect of cyclosporin A (CSA) on the production of cytokines by rheumatoid synovial fibroblasts. Methods. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis and cultured in the presence of CSA. The production of interleukin-10 (IL-10), IL-15, and tumor necrosis factor α (TNFα) by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The expression of IL-10, IL-15, and TNFα messenger RNA (mRNA) in FLS was determined by polymerase chain reaction (PCR). Results. CSA (1-1,000 ng/ml) increased the production of IL-10, but decreased in a dose-dependent manner the levels of IL-15 and TNFα that were spontaneously secreted from FLS. CSA also potently inhibited the production of IL-15 and TNFα stimulated with interferon-γ, IL-1β, or lipopolysaccharide. The inhibitory effect of CSA on IL-15 and TNFα production depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. In a semiquantitative PCR, CSA increased IL-10 mRNA expression but strongly suppressed IL-1β-induced IL-15 and TNFα mRNA expression, indicating that the production of these cytokines by CSA was regulated at the transcriptional level. Results with the calcineurin inhibitor FK-506, but not with the immunosuppressant rapamycin, were similar to those with CSA. Agonists of cAMP displayed an additive effect on the changes produced in the IL-10, IL-15, and TNFα levels by CSA, while a cAMP antagonist almost completely abrogated the effect of CSA, suggesting that cAMP is the major intracellular signal that mediates cytokine regulation by CSA. Conclusion. These results suggest that CSA differentially regulates the production of cytokines by rheumatoid synoviocytes via a cAMP-dependent pathway.

AB - Objective. To determine the direct effect of cyclosporin A (CSA) on the production of cytokines by rheumatoid synovial fibroblasts. Methods. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis and cultured in the presence of CSA. The production of interleukin-10 (IL-10), IL-15, and tumor necrosis factor α (TNFα) by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The expression of IL-10, IL-15, and TNFα messenger RNA (mRNA) in FLS was determined by polymerase chain reaction (PCR). Results. CSA (1-1,000 ng/ml) increased the production of IL-10, but decreased in a dose-dependent manner the levels of IL-15 and TNFα that were spontaneously secreted from FLS. CSA also potently inhibited the production of IL-15 and TNFα stimulated with interferon-γ, IL-1β, or lipopolysaccharide. The inhibitory effect of CSA on IL-15 and TNFα production depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. In a semiquantitative PCR, CSA increased IL-10 mRNA expression but strongly suppressed IL-1β-induced IL-15 and TNFα mRNA expression, indicating that the production of these cytokines by CSA was regulated at the transcriptional level. Results with the calcineurin inhibitor FK-506, but not with the immunosuppressant rapamycin, were similar to those with CSA. Agonists of cAMP displayed an additive effect on the changes produced in the IL-10, IL-15, and TNFα levels by CSA, while a cAMP antagonist almost completely abrogated the effect of CSA, suggesting that cAMP is the major intracellular signal that mediates cytokine regulation by CSA. Conclusion. These results suggest that CSA differentially regulates the production of cytokines by rheumatoid synoviocytes via a cAMP-dependent pathway.

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