title: Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4.
abstract: Although blood monocytes possess significant cytotoxic activity against tumor cells, tumor-infiltrating monocytes are commonly deactivated in cancer patients. Monocytes pre-exposed to tumor cells show significantly decreased expression levels of TNF-alpha, IL-12p40, and IL-1R-associated kinase (IRAK)-1. Activation of the Ser/Thr kinase IRAK-1 is an important event in several inflammatory processes. By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance. In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells. IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures. Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M. Low concentrations of hyaluronan, a cell surface glycosaminoglycan released by tumor cells, also up-regulated IRAK-M. The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line. Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4.
authors.affiliation: Research Unit, Department of Surgical Research, La Paz Hospital, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: del Fresno
authors.forename: Karel
authors.initials: K
authors.lastname: Otero
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gómez-García
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: González-León
authors.forename: Llanos
authors.initials: L
authors.lastname: Soler-Ranger
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.forename: Pedro
authors.initials: P
authors.lastname: Escoll
authors.forename: Rosa
authors.initials: R
authors.lastname: Baos
authors.forename: Luis
authors.initials: L
authors.lastname: Caveda
authors.forename: Felipe
authors.initials: F
authors.lastname: García
authors.forename: Francisco
authors.initials: F
authors.lastname: Arnalich
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking / Q000494:pharmacology; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000502:physiology*; D006820:Hyaluronic Acid / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D019169:Jurkat Cells; D008262:Macrophage Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D011494:Protein Kinases; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases