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Infection and Immunity, June 2009, p. 2488-2498, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00919-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Fasciola hepatica Tegumental Antigen Suppresses Dendritic Cell Maturation and Function{triangledown}

Clare M. Hamilton,1 David J. Dowling,1 Christine E. Loscher,2 Russell M. Morphew,3 Peter M. Brophy,3 and Sandra M. O'Neill1*

Parasite Immune Modulation Group, School of Nursing,1 Immunomodulation Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland,2 Institute of Biological Sciences, Aberystwyth University, Aberystwyth, Ceredigion, Wales, United Kingdom3

Received 24 July 2008/ Returned for modification 28 August 2008/ Accepted 23 March 2009

Parasitic worms and molecules derived from them have powerful anti-inflammatory properties and are shown to have therapeutic effects on inflammatory diseases. The helminth Fasciola hepatica has been reported to suppress antigen-specific Th1 responses in concurrent bacterial infections, thus demonstrating its anti-inflammatory ability in vivo. Here, F. hepatica tegumental antigen (Teg) was shown to significantly suppress serum levels of gamma interferon (IFN-{gamma}) and interleukin-12p70 (IL-12p70) in a model of septic shock. Since dendritic cells (DCs) are a good source of IL-12p70 and critical in driving adaptive immunity, we investigated the effects of F. hepatica Teg on the activation and function of murine DCs. While Teg alone did not induce cytokine production or cell surface marker expression on DCs, it significantly suppressed cytokine production (IL-12p70, IL-6, IL-10, tumor necrosis factor alpha, and nitrite) and cell surface marker expression (CD80, CD86, and CD40) in DCs matured with a range of Toll-like receptor (TLR) and non-TLR ligands. Teg works independently of the TLR4 pathway, since it still functioned in DCs generated from TLR4 mutant and knockout mice. It impaired DC function by inhibiting their phagocytic capacity and their ability to prime T cells. It does not appear to target the common components (extracellular signal-regulated kinase, Jun N-terminal protein kinase, or p38) of the TLR pathways; however, it suppressed the active p65 subunit of the transcription factor NF-{kappa}B in mature DCs, which could explain the impairment of proinflammatory cytokine production. Overall, our results demonstrate the potent anti-inflammatory properties of F. hepatica Teg and its therapeutic potential as an anti-inflammatory agent.

* Corresponding author. Mailing address: Parasite Immune Modulation Group, School of Nursing, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, Ireland. Phone: 353-1-700-5455. Fax: 353-1-700-7919. E-mail: Sandra.ONeill{at}dcu.ie

{triangledown} Published ahead of print on 30 March 2009.

Editor: J. F. Urban, Jr.

Infection and Immunity, June 2009, p. 2488-2498, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00919-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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