Journal Article

TLR signaling-mediated differential histone modification at IL-10 and IL-12 promoter region leads to functional impairments in tumor-associated macrophages

Sayantan Banerjee, Kuntal Halder, Anamika Bose, Parna Bhattacharya, Gaurav Gupta, Santanu Karmahapatra, Shibali Das, Shubho Chaudhuri, Suchandra Bhattacharyya Majumdar and Subrata Majumdar

in Carcinogenesis

Volume 32, issue 12, pages 1789-1797
Published in print December 2011 | ISSN: 0143-3334
Published online September 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr208
TLR signaling-mediated differential histone modification at IL-10 and IL-12 promoter region leads to functional impairments in tumor-associated macrophages

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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.

Journal Article.  6675 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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