p53 in the immune response: the ace up the sleeve
The tumor suppressor p53 is a sequence-specific transcription factor that is activated in response to various cellular stresses such as DNA damage, oncogene over-expression and associated uncontrolled cell proliferation. p53 functions mainly as a transcription factor and is a key component in preventing cancer development through regulation of apoptosis, cell cycle and senescence genes thereby helping to maintain genome stability within an organism. Alterations of p53 function through mutation or misregulation in the p53 network are common features in human cancers with over 80-90% of tumors having an altered p53 pathway [
In this review we explore the interactions between p53 and the immune system. The focus is mainly on the role that wild type (WT) p53 plays in immune-related processes such as inflammation, innate and adaptive responses as well as functional interactions of p53 with NF-kB, which is considered a key regulator in immune responses. Emphasis is placed on p53 as a transcription factor in modulating expression of target genes involved in immunity pathways (see Figure 1).
The immune system is a collection of biological processes whose tasks in preventing disease include identification and destruction of pathogens and tumor cells. Given the broad diversity in p53 controls and functions, it is not surprising that p53 touches multiple aspects of immunity. For example, DNA damage can trigger p53 responses that help orchestrate clearance of damaged cells via the innate immune system [
p53 also appears to be involved during the generation of immune cells. In agreement with its role as a modulator in stem cell appearance, p53 can limit expansion of hematopoietic stem cells (HSC) [
Inflammation and p53: maintaining homeostasis
Inflammation, a common immune response, is a protective first-responder attempt to remove injurious stimuli and to initiate healing. It is a complex signal-mediated reaction by vascular tissues to cellular insults such as pathogens and infectious agents, toxins, physical stress or damaged cells. Acute inflammation is an important mode of immune response, while chronic inflammation can cause tissue destruction or even autoimmunity.
p53 has several roles in inflammation including modifying cell growth and cellular behavior in response to DNA and inflammatory stressors. p53 is activated by DNA damage that is induced by both ROS and reactive nitrogen species (NOS) that are produced during inflammation [
As a transcription factor, p53 can modulate expression of several genes encoding enzymes involved in both production or elimination of reactive species contributing to inflammation including, for example, up-regulation of the antioxidant glutathione peroxidase (GPX1)[
Thus, p53 can play a significant role in modulating intracellular ROS/ NOS levels to aid in appropriate balance of the inflammatory responses. In addition, since p53 is subject to modifications in the presence of reactive compounds, it can be considered a cellular sensor of redox changes [
The relationship between p53 and pathogenesis of inflammation-associated cancer and other immune related diseases extends beyond induction/restriction of inflammatory responses, all of which can be affected by p53 expression, mutation or alterations in its regulatory pathway. For example, there is greater invasion of inflammatory and fibroblast cells into IR damaged tissues in p53-null compared to WT mice [
Innate and adaptive immune responses in p53 null mice can be skewed toward pro-inflammation, suggesting p53 may act as a negative regulator of inflammation (34-40). Additionally, p53 null mice are susceptible to autoimmune diseases including collagen-induced arthritis [
p53, viral infections and immune responses
Up-regulation of p53 in response to viral infections is a part of host cell defenses. For example, increased p53-dependent apoptosis can reduce viral replication [
Since the discovery over 30 years ago of p53 as a binding partner of SV40 LTag [
The ability of viruses to alter p53 functions and pathways is an important step in their establishment and pathogenesis in animal hosts. Described in Table 1 are examples of viral proteins that interact with p53. Viruses can disrupt p53 functions either directly or through cellular factors involved in downstream activities so as to override cell-cycle checkpoints or protect cells from p53-dependent apoptosis. p53 can be sequestered and/or inactivated by posttranslational modifications (phosphorylation, ubiquitination) induced by viral proteins or by modulation of host enzymes such as Mdm2 that promote proteasome degradation of p53 (see review by Lazo and Santos [
In response to viral infections, one of the most efficient and rapid responses triggered by the immune system is induction of type I interferon mediated signaling. This response involves activation of the STAT (signal transducer and activator of transcription) signaling pathway and subsequent expression of antiviral genes. Several years ago, the seminal discovery of Takaoka et al. [
Alternatively, p53 can influence both IFN production and signaling, enhancing the antiviral response through direct transcriptional up-regulation of several IFN-inducible genes. Included are transcriptional activators such as interferon regulatory factor 9 (IRF9) [
Overall, these findings have established important roles for p53 transcriptional activities in host defense against viral infection and support the relevance of p53 in antiviral innate immunity.
p53 general influence on immune response pathways
While there is substantial evidence that p53 protects against inflammation (mostly under chronic conditions), recent studies in mouse and human cells reveal that p53 may promote acute inflammation and immune responses ([
p53 can influence several innate and adaptive immune pathways through regulation of genes involved in signaling (chemokines, interleukins), pathogen recognition (TLRs) and activation of specific subsets of immune cells such as T and B lymphocytes, NK cells and macrophages. Interleukins and chemokines are signaling molecules that affect a variety of cellular functions and are stimulated when tissue homeostasis is altered. Both are mediators of inflammation and play critical roles in host defense by attracting and activating specific subsets of effector leukocytes, cells from the monocyte/macrophage lineage as well as natural killer (NK) cells.
Expression of chemokines and cytokines are subject to p53, depending on stimulus and cell type. p53 can increase transcription of several cytokines involved in innate immunity including colony-stimulating factor 1 (CSF1) and monocyte chemotactic protein (MCP1), chemokine CXC motif ligand (CXCL1) and interleukin 15 (IL-15) that attract macrophages, neutrophils, and natural killer cells, contributing to immune elimination of senescent cells [
Chemokines also can influence p53 activities. For example, the macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and pro-inflammatory function by inhibiting p53 [
The expression of several surface markers on cells involved in immune responses is subject to p53 regulation. Genotoxic activation of p53 leads to up-regulation of intracellular-adhesion molecule-1 (ICAM-1) mRNA and protein [
Boosting innate and adaptive immune responses with p53
Recently, employing a genome-wide in silico search we found that most members of the human Toll Like Receptor (TLR) gene family contain potential p53 targets [
Using primary lymphocytes and alveolar macrophages from healthy subjects [
p53 also has transcriptional targets in antigen cell-signaling pathways of T and B lymphocytes. The TAP1 protein (transporter associated with antigen processing) is required for the major histocompatibility complex (MHC) class I antigen presentation pathway that plays a key role in host tumor surveillance. In response to DNA damage, TAP1 expression is induced by p53 in cooperation with its family member protein p73. This up-regulation enhances transport of MHC class I peptides, expression of surface MHC-peptide complexes and activation of the MHC class I pathway [
Regulation of the NK cells activities provides another example of p53 influence on the host immune system. These cells are specialized immune cells that eliminate foreign, stressed, transformed and senescent cells through specialized surface receptors, such as NKG2D [
Innate and adaptive immunity are also connected to p53 through transcriptional regulation of microRNAs (miRNAs), which are small non-coding endogenous RNAs that bind complementary sequences of target mRNAs and regulate translation of specific genes. miRNAs affect inflammation and cancer [
p53 as a direct target in cancer immunotherapy
Since the immune system must distinguish between self and non-self antigens, p53 has been considered a target for immunotherapy. First identified in the sera of cancer patients more than 30 years ago [
p53 and NF-kB cross-talk in immune responses
As described above, roles for p53 in immunity are continually emerging. However, these must be considered in light of the other well-established modulators of immunity and inflammation especially NF-kB, a master regulator of immune responses.
Most discussions of p53 and NF-kB interactions have focused on their roles in cancer. While p53 and NF-kB are generally considered to be opposing factors where p53 promotes apoptosis while NF-kB enhances survival (reviewed in [
The complicated relationship between p53 and NF-kB is also seen in the context of immune responses. p53 can play an inhibitory role in NF-kB signaling and consequently the inflammatory response. For example, p53 inhibits IKK β and NF-kB mediated transactivation in IgE-mediated degranulation of mast cells and anaphylaxis [
Positive p53/NF-kB relationships in the immune response have also been described. p53 stabilization by treatment of cells with Nutlin-3 was able to enhance retrovirus-induced apoptosis of host cells in part through augmented activation of NF-kB [
p53 and NF-kB in senescence
In recent years, both p53 and NF-kB have been shown to play a role in senescence (irreversible cell cycle arrest) based on a strong link with inflammation [
The connection between p53 and immunity: concluding remarks
p53 has an important role in innate and adaptive immune responses where activation of p53 can be both beneficial and detrimental. In addition to cancer, there are many infectious disease implications, as we had proposed for a loop between pathogen detection by TLRs, inflammation and p53 induction [
The p53/immune interaction is especially relevant to cancer as indicated in a recent review of “hallmarks of cancer” by Hanahan and Weinberg [
Although there are nearly 30 immune-related genes (including miRNAs) targeted by p53, many new targets are expected to be identified in the near future through genome-wide methods. The combination of chromatin immunoprecipitation (ChIP) with high throughput sequencing (ChIP-seq) and expression analysis has already been used to map sites of p53 binding among the hundreds of thousands of potential target sequences in the human genome and to identify candidate p53 target genes [
Acknowledgements
We thank Drs. Mike B. Fessler and Stavros Garantziotis for providing insightful comments and suggestions on the manuscript. This work was supported by the National Institute of Environmental Health Sciences, National Institutes of Health Intramural Research Program (Z01-ES065079 to MAR).
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