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Immunosuppressive Effects and Mechanisms of Leflunomide in Dengue Virus Infection of Human Dendritic Cells

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Abstract

Background

Dengue virus (DENV) infection is a serious public health issue without specific treatment. We examined the potential immunomodulatory effects of leflunomide, a dihydroorotate dehydrogenase inhibitor commonly prescribed for arthritis, in DENV-stimulated monocyte-derived dendritic cells (mo-DCs).

Methods

mo-DCs were prepared from purified monocytes. Cytokine and chemokine concentrations were determined by enzyme-linked immunosorbent assay. Expression of cell surface markers or viral E protein was measured by flow cytometry. The activation of transcription factors and kinases was determined by electrophoretic mobility shift assays, Western blotting, or immunoprecipitation kinase assays. Chemotaxis assays were used to determine cell migration.

Results

Leflunomide at therapeutic concentrations inhibited cytokine and chemokine production from DENV-infected mo-DCs. Leflunomide suppressed mo-DC maturation by downregulating the expression of both CD80 and CD86. In addition, leflunomide inhibited DENV-induced mo-DC migration and mo-DC response to chemoattractants CCL19 and CCL21. Inhibition of mo-DC migration was likely due to the suppression of CCR7 expression on mo-DCs. These events were associated with the suppression of nuclear factor kappa B and activator protein-1 signaling pathways by leflunomide.

Conclusions

Leflunomide preserves immunosuppressive effects, inhibiting activation of DENV-stimulated mo-DCs. Leflunomide may be helpful in the development of therapeutics for DENV infection.

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Abbreviations

DENV:

dengue virus

mo-DCs:

dendritic cells

DHF:

dengue hemorrhagic fever

DSS:

dengue shock syndrome

DHODH:

dihydroorotate dehydrogenase

IKK:

IκB kinase

NF-κB:

nuclear factor kappa B

MAPK:

mitogen-activated protein kinase

JNK:

c-Jun N-terminal kinase

ERK:

extracellular signal-regulated kinase

AP-1:

activator protein-1

MCP-1:

monocyte chemoattractant protein-1

MIP-1α:

macrophage inflammatory protein-1α

RANTES:

regulated upon activation, normal T cell expressed and secreted

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Acknowledgements

This report was supported by a grant from the Institutional Collaboration Projects raised by both Chi Mei Medical Center and National Defense Medical Center (CMNDMC99 and CMNDMC10008) as well as from Institute of Preventive Medicine, National Defense Medical Center. The authors’ work was supported in part by grants from the National Science Council (NSC 96-2314-B-016-015-MY3, NSC 96-2314-B-400-003-MY2, and NSC 98-2314-B-400-002-MY3).

Competing Interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli County, 350, Taiwan, Republic of China

    Wan-Lin Wu, Ling-Jun Ho & Seng-Ting Hsu

  2. Rheumatology, Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan, Republic of China

    Pei-Chih Chen

  3. Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China

    Yi-Ting Tsai

  4. Division of Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, 114, Taipei, Taiwan, Republic of China

    Deh-Ming Chang & Jenn-Haung Lai

  5. Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan

    Jenn-Haung Lai

  6. Graduate Institute of Basic Medical Science, PhD Program for Aging, China Medical University, Taichung, 40402, Taiwan, Republic of China

    Ling-Jun Ho

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  1. Wan-Lin Wu
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Correspondence to Jenn-Haung Lai.

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Wu, WL., Ho, LJ., Chen, PC. et al. Immunosuppressive Effects and Mechanisms of Leflunomide in Dengue Virus Infection of Human Dendritic Cells. J Clin Immunol 31, 1065–1078 (2011). https://doi.org/10.1007/s10875-011-9578-7

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  • DOI: https://doi.org/10.1007/s10875-011-9578-7

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