Published online before print February 24, 2009
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Article |
Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway
@ To whom correspondence should be addressed. E-mail: mosioud{at}medisin.uio.no.
Human bone marrow (BM) hematopoietic cells were found recently to express functional TLRs and TLR signaling-induced cytokine production and cell differentiation. Here, we have asked whether signals other than those from TLRs could instruct BM CD34+ cells to produce cytokines and differentiate by uncovering the role of nucleotide oligomerization domain (Nod)-like receptor (NLR) family members, NOD1 and NOD2. We show that NOD2 is expressed by freshly isolated human BM CD34+ cells, whereas the expression of its close homologue NOD1 is very weak, if it has any expression at all. Stimulation of the cells by the muramyl dipeptide (MDP), but not its inactive D–D enantiomer, is sufficient to trigger the expression of TNF-
, GM-CSF, CD11c, CD14, CD206, and the transcription factor PU.1, which is indispensable for cell differentiation toward the myeloid lineage. MDP differentiated CD11c+ cell subset-activated T cells in MLR. Furthermore, NOD2 stimulation enhanced the CD34+ response to TLR ligands (e.g., LPS, palmitoyl-3-cysteine-serine-lysine-4) and increased intracellular -defensin protein levels. Although the best-known function of NLRs involves mature cells, our data highlight for the first time the functionality of these receptors in human BM CD34+ hematopoietic cells.
Key Words: hematopoiesis • myeloid cells • Toll-like receptors • defensins
