Source:http://linkedlifedata.com/resource/pubmed/id/21278795
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
21
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| pubmed:dateCreated |
2011-5-26
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| pubmed:abstractText |
Tumor-associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME, including tumor growth factor-? (TGF-?), allow tumors to circumvent host-mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells, whose activation triggers the production of molecules required for anti-tumoral responses. Interleukin (IL) receptor-associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. In this study, we show that TAMs express significantly higher levels of IRAK-M compared with peritoneal macrophages in a syngeneic mouse model of lung cancer. Subcutaneous implantation of Lewis lung carcinoma cells in IRAK-M(-/-) mice resulted in a five-fold reduction in tumor growth as compared with tumors in wild-type (WT) animals. Furthermore, compared with WT TAMs, TAMs isolated from IRAK-M(-/-) mice displayed features of a classically activated (M1) rather than alternatively activated (M2) phenotype, as manifest by greater expression of IL-12, interferon-? (IFN-?) and inducible nitric oxide synthase. Human lung cancer cells induced IRAK-M expression in human peripheral blood mononuclear cells (PBMCs) when co-cultured together. Tumor cell-induced expression of IRAK-M was dependent on the activation of TGF-? pathway. Similarly, treatment of human PBMCs or mouse macrophage cell line, RAW 264.4, with TGF-?, induced IRAK-M expression. Interestingly, IRAK-M gene expression in 439 human lung adenocarcinoma tumors correlated with poor survival in patients with lung cancer. Together, our data demonstrates that TGF-?-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/IRAK3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1 Receptor-Associated...,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-12,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
1476-5594
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
26
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| pubmed:volume |
30
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
2475-84
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| pubmed:dateRevised |
2011-9-26
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| pubmed:meshHeading |
pubmed-meshheading:21278795-Animals,
pubmed-meshheading:21278795-Blotting, Western,
pubmed-meshheading:21278795-Carcinoma, Lewis Lung,
pubmed-meshheading:21278795-Cell Line,
pubmed-meshheading:21278795-Cell Line, Tumor,
pubmed-meshheading:21278795-Cells, Cultured,
pubmed-meshheading:21278795-Coculture Techniques,
pubmed-meshheading:21278795-Female,
pubmed-meshheading:21278795-Gene Expression Profiling,
pubmed-meshheading:21278795-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:21278795-Humans,
pubmed-meshheading:21278795-Interferon-gamma,
pubmed-meshheading:21278795-Interleukin-1 Receptor-Associated Kinases,
pubmed-meshheading:21278795-Interleukin-12,
pubmed-meshheading:21278795-Lung Neoplasms,
pubmed-meshheading:21278795-Macrophages,
pubmed-meshheading:21278795-Macrophages, Peritoneal,
pubmed-meshheading:21278795-Male,
pubmed-meshheading:21278795-Mice,
pubmed-meshheading:21278795-Mice, Inbred C57BL,
pubmed-meshheading:21278795-Mice, Knockout,
pubmed-meshheading:21278795-Monocytes,
pubmed-meshheading:21278795-Oligonucleotide Array Sequence Analysis,
pubmed-meshheading:21278795-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:21278795-Survival Analysis,
pubmed-meshheading:21278795-Transforming Growth Factor beta
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| pubmed:year |
2011
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| pubmed:articleTitle |
TGF-?-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth.
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| pubmed:affiliation |
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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