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Toll-like Receptor-4 Is Up-Regulated in Hematopoietic Progenitor Cells and Contributes to Increased Apoptosis in Myelodysplastic Syndromes

Authors' Affiliations: ¹ Department of Pathophysiology, Medical School, National University of Athens, and ² Department of Immunology and Transplantations, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece

Requests for reprints: Michael Voulgarelis, Department of Pathophysiology, Medical School, National University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece. Phone: 30-210-746-2648; Fax: 30-210-746-2664; E-mail: mvoulgar{at}med.uoa.gr.

Purpose: To investigate the function and expression of Toll-like receptors (TLR) in bone marrow cells of myelodysplastic syndrome (MDS) patients and to examine their involvement in the apoptotic phenomenon characterizing MDS hematopoiesis.

Experimental Design: TLR mRNA and protein expression was investigated in bone marrow cell populations of MDS patients and controls. TLR-4 ability to recognize lipopolysaccharide and up-regulate self mRNA and protein expression was examined. Tumor necrosis factor involvement in the constitutive and lipopolysaccharide (LPS)-induced TLR expression was also evaluated. Possible correlation between TLR-4 overexpression and apoptosis was investigated by simultaneous staining with Annexin V and TLR-4.

Results: TLR-2 and TLR-4 are expressed in almost all bone marrow cell lineages including megakaryocytes, erythroid cells, myeloid precursors, monocytes, and B lymphocytes and are up-regulated in MDS patients compared with controls. In hematopoietic CD34⁺ cells, TLR-4 is also expressed and significantly up-regulated at both the mRNA and protein levels. Treatment with an anti–tumor necrosis factor antibody reduces both constitutive and LPS-induced TLR-4 levels. Increased TLR-4 expression correlates with increased apoptosis as TLR-4 is almost exclusively found in apoptotic bone marrow mononuclear and CD34⁺ cells. The addition of the TLR-4 ligand LPS further enhances the apoptosis of these cells.

Conclusions: TLR-4 and other TLRs are significantly up-regulated in MDS patients whereas TLR-4 is involved in promoting apoptosis, possibly contributing to MDS cytopenia.