Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4.
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.
del Fresno
Carlos
C
Research Unit, Department of Surgical Research, La Paz Hospital, Madrid, Spain.
Otero
Karel
K
Gómez-García
Lourdes
L
González-León
Maria Carmen
MC
Soler-Ranger
Llanos
L
Fuentes-Prior
Pablo
P
Escoll
Pedro
P
Baos
Rosa
R
Caveda
Luis
L
García
Felipe
F
Arnalich
Francisco
F
López-Collazo
Eduardo
E
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*
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