title: Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growth.
abstract: IRAK-M is a negative regulator of innate immunity signaling processes. Although attenuation of innate immunity may help to prevent excessive inflammation, it may also lead to compromised immune surveillance of tumor cells and contribute to tumor formation and growth. Here, we demonstrate that IRAK-M(-/-) mice are resistant to tumor growth upon inoculation with transplantable tumor cells. Immune cells from IRAK-M(-/-) mice are responsible for the anti-tumor effect, since adoptive transfer of splenocytes from IRAK-M(-/-) mice to wild type mice can transfer the tumor-resistant phenotype. Upon tumor cell challenge, there are elevated populations of CD4(+) and CD8(+) T cells and a decreased population of CD4(+) CD25(+)Foxp3(+) regulatory T cells in IRAK-M(-/-) splenocytes. Furthermore, we observe that IRAK-M deficiency leads to elevated proliferation and activation of T cells and B cells. Enhanced NFkappaB activation directly caused by IRAK-M deficiency may explain elevated activation of T and B cells. In addition, macrophages from IRAK-M(-/-) mice exhibit enhanced phagocytic function toward acetylated LDL and apoptotic thymocytes. Collectively, we demonstrate that IRAK-M is directly involved in the regulation of both innate and adaptive immune signaling processes, and deletion of IRAK-M enhances host anti-tumor immune response.
authors.affiliation: Laboratory of Innate Immunity and Inflammation, Department of Biological Sciences, Fralin Biotechnology Center, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Qifa
authors.initials: Q
authors.lastname: Xie
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Jianxia
authors.initials: J
authors.lastname: Wang
authors.forename: Ingred
authors.initials: I
authors.lastname: Wilson
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D020672:I-kappa B Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*; D010587:Phagocytosis; D011499:Protein Processing, Post-Translational; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse