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-Dependent Apoptosis in Human Monocyte-Derived Dendritic Cells by Microfilariae of Brugia malayi1
* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, and
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20872;
Baylor Institute for Immunology Research, Dallas, TX 75204; and
Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840
Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24–96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, whereas mf exposure did not induce apoptosis in macrophages. Interestingly, 48-h exposure of DC to mf induced mRNA expression of the proapoptotic gene TRAIL and both mRNA and protein expression of TNF-
. mAb to TRAIL-R2, TNF-R1, or TNF- partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. The mf also induced gene expression of BH3-interacting domain death agonist and protein expression of cytochrome c in DC; mf-induced cleavage of BH3-interacting domain death agonist could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF--dependent fashion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Because R.T.S., P.G.V., L.M., F.M., D. C., D.D., R.M.S., and T.B.N. are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the National Institutes of Health reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. Rights can be established outside of the U.S. subject to a government use license.
2 Address correspondence and reprint requests to Dr. Roshanak Tolouei Semnani, National Institute of Allergy and Infectious Diseases, 4 Center Drive, Room 4/B105, National Institutes of Health, Bethesda, MD 20892. E-mail address: rsemnani{at}niaid.nih.gov
3 Abbreviations used in this paper: DC, dendritic cell; Bid, BH3-interacting domain death agonist; Ct, threshold cycle; FADD, Fas-associated death domain protein; M
, macrophage; mf, live microfilariae; PI, propidium iodide; tBid, truncated Bid; TRAF, TNFR-associated factor.
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