The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells

Kubo Satoshi Kubo, Kunihiro Yamaoka, Masahiro Kondo, Kaoru Yamagata, Jidong Zhao, Shigeru Iwata, Yoshiya Tanaka

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Objective: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. Methods: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. Results: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1ß production without affecting transforming growth factor (TGF)-ß and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. Conclusions: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
DOIs
Publication statusAccepted/In press - 2013 Sep 6
Externally publishedYes

Fingerprint

Janus Kinases
T-cells
Dendritic Cells
Monocytes
T-Lymphocytes
Interferon Type I
Indoleamine-Pyrrole 2,3,-Dioxygenase
Lipopolysaccharides
Interferon Regulatory Factor-7
Interferon alpha-beta Receptor
tofacitinib
Lymphocytes
Transforming Growth Factors
HLA-DR Antigens
Interleukin-1
Human Activities
Interleukin-10
Interleukin-6
Rheumatoid Arthritis
Transcription Factors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology
  • Rheumatology

Cite this

The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. / Satoshi Kubo, Kubo; Yamaoka, Kunihiro; Kondo, Masahiro; Yamagata, Kaoru; Zhao, Jidong; Iwata, Shigeru; Tanaka, Yoshiya.

In: Annals of the Rheumatic Diseases, 06.09.2013.

Research output: Contribution to journalArticle

Satoshi Kubo, Kubo ; Yamaoka, Kunihiro ; Kondo, Masahiro ; Yamagata, Kaoru ; Zhao, Jidong ; Iwata, Shigeru ; Tanaka, Yoshiya. / The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. In: Annals of the Rheumatic Diseases. 2013.
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abstract = "Objective: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. Methods: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with na{\"i}ve CD45RA-positive T cells. Results: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1{\ss} production without affecting transforming growth factor (TGF)-{\ss} and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. Conclusions: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.",
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T1 - The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells

AU - Satoshi Kubo, Kubo

AU - Yamaoka, Kunihiro

AU - Kondo, Masahiro

AU - Yamagata, Kaoru

AU - Zhao, Jidong

AU - Iwata, Shigeru

AU - Tanaka, Yoshiya

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N2 - Objective: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. Methods: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. Results: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1ß production without affecting transforming growth factor (TGF)-ß and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. Conclusions: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.

AB - Objective: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. Methods: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. Results: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1ß production without affecting transforming growth factor (TGF)-ß and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. Conclusions: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.

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