NOD2/CARD15 on bone marrow CD34+ hematopoietic cells mediates induction of cytokines and cell differentiation.
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. Stimulation of the cells by the muramyl dipeptide (MDP), but not its inactive D-D enantiomer, is sufficient to trigger the expression of TNF-alpha, 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 alpha-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.
Sioud
Mouldy
M
Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, HN-0310, Oslo, Norway. mosioud@medisin.uio.no
Fløisand
Yngvar
Y
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006413:Hematopoietic System / Q000166:cytology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000819:agonists; D015854:Up-Regulation / Q000187:drug effects; D023084:alpha-Defensins / Q000378:metabolism
D018952:Antigens, CD34; D039521:CD11c Antigen; D016207:Cytokines; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D023084:alpha-Defensins; D000119:Acetylmuramyl-Alanyl-Isoglutamine