The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks

Abstract

In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond “guardian of the genome.” Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor ( TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings—demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress—have many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks.

Author Summary

Among the most prominently studied regulators of gene function is the p53 tumor suppressor, which has many roles in human biology. The transcriptional master regulator p53 directly targets expression of >200 genes. Previously, we sought to define the p53 network in terms of functionality, specifically the ability of target response element sequences (REs) to support p53 transactivation. Here we identify p53 target canonical and noncanonical REs in the family of Toll-like Receptor (TLR) innate immune response genes and establish p53 regulation of most TLR genes. We address p53 responsiveness in primary human lymphocytes and alveolar macrophages collected from healthy volunteers. Notably, all TLR genes show responses to DNA damage, and most are p53-mediated. However, there is considerable variability between individuals, suggesting that DNA and p53 metabolic stresses can markedly differ in impact on the innate immune system as well as downstream appearance of cytokines. Indeed, we report a SNP in a p53 RE within the TLR8 promoter that alters p53 responsiveness in primary human cells. Furthermore, the p53-mediated expression of TLRs is unique to primates. Overall, these findings identify a new, pivotal role for the well-known human tumor suppressor p53, namely, integration of DNA damage and innate immune responses.