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 (TAMs) 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, co-regulate induction of pro-inflammatory genes in primary human monocytes and macrophages. Using Nutlin-3 as a tool, we demonstrate that p53 and NF-κB rapidly and highly induce 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. Additionally, 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 [TCMs]). Compared to 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 pro-inflammatory 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.

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

“…Recent studies have shown that TAM-like PBMo-derived macrophages stimulated with TCM such as those found in breast, ovarian, and colorectal cancer produced these factors. 16,[38][39][40] In the present study, GDF15 was upregulated in PBMo-derived macrophages stimulated with TECM, whereas, to our knowledge, it has not been reported that TAM-like PBMo-derived macrophages stimulated with other TCMs secreted GDF15. Expression of GDF15 was not detected in cytokine-induced M2-polarized macrophages such as IL-4 and IL-13 (Supplementary Figure 1).…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Inflammatory responses to exposures of p53-activating chemotherapeutic drugs were measured in immune cells from the blood and lungs of healthy volunteers [124]. Various proinflammatory genes had enhanced expression after exposure to the chemotherapeutics which required both p53 and NF-κB.…”

“…4. Various nanoformulations for co-delivery of therapeutics with normalized pharmacokinetics and pharmacodynamics, including self-assembled nanoscale coordination polymer [158], cholesterol-based chimeric nanoparticle [157], thermosensitive hydrogel [123], mesoporous silica nanoparticle [125], and liposomes [124].…”

A unique role for p53 in the regulation of M2 macrophage polarization

“…Indeed, recent reports suggest that p53 may indeed have such a role to play in TAM biology. 19,20 A low concentration of endotoxin triggers tolerance, which involves the reprogramming of macrophages. 21 Prior exposure to endotoxin can be an evolutionary advantage because it triggers a selective shutdown of the production of proinflammatory cytokines (from M1 macrophages), which cause tissue damage and preserves the generation of protective antiinflammatory mediators (from M2 macrophages).…”