title: TLR signaling-mediated differential histone modification at IL-10 and IL-12 promoter region leads to functional impairments in tumor-associated macrophages.
abstract: Tumor-associated macrophages (TAM) are severely compromised for the induction of proinflammatory mediators following toll-like receptor (TLR) activation. Here, we reported that the defective TLR response in TAM was due to the malfunctioning of the myeloid differentiation primary response gene 88 (MyD88)-dependent signaling cascade in concert with downregulation of tumor necrosis factor receptor-associated factor (TRAF) 6 and interleukin-1 receptor-associated kinase (IRAK) 1. However, the expression of toll-interleukin1 receptor domain-containing adapter-inducing interferon beta (TRIF) and TRAF 3, which act via the TRIF-dependent pathway of TLR signaling, were found to be unaffected in TAM. Although, TRIF-mediated signal inducers, lipopolysaccharide or poly (I:C), induced high level of extracellular signal-regulated kinase (ERK)-1/2 mitogen-activated protein kinase (MAPK) phosphorylation, but they were failed to induce significant p38MAPK phosphorylation in TAM. Consequently, ERK-1/2-dependent histone phosphorylation at the IL-10 promoter elicited enhanced interleukin (IL)-10 production by TAM. Whereas, the lack of transcription favorable histone phosphorylation at the IL-12 promoter was accompanied with a very low amount of IL-12 expression in TAM. Moreover, ERK-1/2 MAPK activation resulted in enhanced IRAK M induction in TAM, a specific inhibitor of MyD88 pathway. Therefore, for the first time, we decipher an unexplored TLR signaling in TAM where ERK-1/2 activation in a MyD88-independent pathway results in transcription favorable histone modification at the IL-10 promoter region to enhance IL-10-mediated immunosuppression. Additionally, by enhancing IRAK M induction, it also polarizes TAM toward a more immunosuppressive form.
authors.affiliation: Division of Molecular Medcine, Bose Institute, P1/12 C.I.T. scheme VIIM, Kolkata 700054, India.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Banerjee
authors.forename: Kuntal
authors.initials: K
authors.lastname: Halder
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.forename: Parna
authors.initials: P
authors.lastname: Bhattacharya
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gupta
authors.forename: Santanu
authors.initials: S
authors.lastname: Karmahapatra
authors.forename: Shibali
authors.initials: S
authors.lastname: Das
authors.forename: Shubho
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Suchandra
authors.initials: S
authors.lastname: Bhattacharyya Majumdar
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006657:Histones / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics*; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D006657:Histones; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D011494:Protein Kinases