title: p53 and NF-κB coregulate proinflammatory gene responses in human macrophages.
abstract: Macrophages are sentinel immune cells that survey the tissue microenvironment, releasing cytokines in response to both exogenous insults and endogenous events such as tumorigenesis. Macrophages mediate tumor surveillance and therapy-induced tumor regression; however, tumor-associated macrophages (TAM) and their products may also promote tumor progression. Whereas NF-κB is prominent in macrophage-initiated inflammatory responses, little is known about the role of p53 in macrophage responses to environmental challenge, including chemotherapy or in TAMs. Here, we report that NF-κB and p53, which generally have opposing effects in cancer cells, coregulate induction of proinflammatory genes in primary human monocytes and macrophages. Using Nutlin-3 as a tool, we demonstrate that p53 and NF-κB rapidly and highly induce interleukin (IL)-6 by binding to its promoter. Transcriptome analysis revealed global p53/NF-κB co-regulation of immune response genes, including several chemokines, which effectively induced human neutrophil migration. In addition, we show that p53, activated by tumor cell paracrine factors, induces high basal levels of macrophage IL-6 in a TAM model system [tumor-conditioned macrophages (TCM)]. Compared with normal macrophages, TCMs exhibited higher p53 levels, enhanced p53 binding to the IL-6 promoter, and reduced IL-6 levels upon p53 inhibition. Taken together, we describe a mechanism by which human macrophages integrate signals through p53 and NF-κB to drive proinflammatory cytokine induction. Our results implicate a novel role for macrophage p53 in conditioning the tumor microenvironment and suggest a potential mechanism by which p53-activating chemotherapeutics, acting upon p53-sufficient macrophages and precursor monocytes, may indirectly impact tumors lacking functional p53.
authors.affiliation: Authors' Affiliations: Laboratory of Molecular Genetics, Biostatistics Branch, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park; and Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Lowe
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Bushel
authors.forename: Maria
authors.initials: M
authors.lastname: Shatz
authors.forename: Erin L
authors.initials: EL
authors.lastname: Kirk
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
mesh_terms: D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007111:Immunity, Cellular / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D046228:Microarray Analysis; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology
chemical_list: D007093:Imidazoles; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010879:Piperazines; C495901:TP53 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3
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