Inflammation and Stretch: Mechanics of Immunity Meet at p53

We often picture inflammation as a storm of cytokines — TNF-α, IL-6, interferons — released by immune cells. But inflammation is more than chemistry: it reshapes mechanics at the cellular and tissue level resulting in stiffening blood vessels, increasing vascular tone, and causing edema. Inflammation forces tissues into stretch and strain (Pober & Sessa, 2007: ; Schiffrin, 2014:).

Cells sense this stretch as stress. Endothelial and smooth muscle cells don’t simply absorb it — they activate protective and inflammatory pathways. At the crossroads of this response is p53, the well-known “guardian of the genome,” which here becomes a translator of mechanical stress into immune tone.

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Inflammation Creates Stretch

At the onset of inflammation, immune cells like neutrophils and macrophages release cytokines (TNF-α, IL-1β, IL-6) and reactive oxygen species. These trigger several physical consequences:

• Vasoconstriction: cytokines reduce nitric oxide and increase endothelin-1, raising intravascular pressure (Virdis & Schiffrin, 2003:).

• Edema: increased vascular permeability leads to tissue swelling, compressing vessels from the outside (Ley et al., 2007:).

• Stiffening: macrophages and T cells drive fibrosis through collagen deposition and TGF-β, making vessel walls less compliant (Intengan & Schiffrin, 2000:).

Together, these changes simulate mechanical stretch at the microvascular level.

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Stretch Activates p53

Mechanical strain is known to activate p53 through oxidative stress, DNA damage responses, and ER stress (Madrazo & Kelly, 2008:). In vascular cells:

• Endothelial cells: p53 can reduce IL-6 (by competing with NF-κB) but enhance interferon signaling (via STAT1/IRF9) (Vousden & Prives, 2009:).

• Smooth muscle cells: p53 drives cell cycle arrest and senescence, stabilizing the vessel wall but promoting stiffness (Giaccia & Kastan, 1998:).

• Immune cells (including NK cells): p53 regulates survival, apoptosis, and cytokine output, balancing activation against exhaustion (Menendez et al., 2009:).

Thus, p53 acts as a convergence point where inflammation-induced mechanics meet immune regulation.

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NK Cells: Partners in the Loop

Natural killer (NK) cells illustrate how mechanics and immunity are intertwined.

• Early NK response (hours to day 1): NKs are rapidly recruited by cytokines and stress ligands, releasing IFN-γ and TNF-α, and injuring stressed endothelial cells. Here, p53 activity in vascular cells biases the environment toward interferon signaling, supporting NK activation (Vivier et al., 2011:).

• Transition phase (days): macrophages and dendritic cells dominate, producing IL-6 and TNF-α. p53 in these myeloid cells restrains NF-κB–driven cytokines while promoting type I interferons, further priming NK cells (Sakaguchi et al., 2020:).

• Late NK response (days–weeks): NKs amplify chronic inflammation through IFN-γ, TNF-α, and antibody-dependent cytotoxicity. In this phase, p53 may push NKs toward exhaustion, while senescent endothelial and smooth muscle cells release SASP factors (IL-6, IL-8) that perpetuate the cycle (Coppe et al., 2010:).

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The Feedback Loop

Inflammation and stretch are not separate. They form a self-reinforcing loop:

1. Inflammation → Stretch: cytokines alter vascular tone, stiffness, and permeability.

2. Stretch → p53 activation: p53 senses the stress in endothelial, smooth muscle, and NK cells.

3. p53 → Immune tone: restrains IL-6, enhances interferons, and modulates NK cell survival and cytokine balance.

4. NK cells → More inflammation: IFN-γ and TNF-α amplify vascular injury and immune recruitment.

This cycle explains why hypertension, vascular inflammation, and immune activation are so tightly linked.

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Why It Matters

Understanding how inflammation leads to mechanical stress, and how p53 links stretch to immunity, may open therapeutic opportunities:

• Reducing vascular stiffness could break the loop between mechanics and inflammation.

• Modulating p53 might rebalance cytokine outputs (lowering IL-6 while supporting interferons).

• Preserving NK cell function under stress could sustain protective immunity without driving exhaustion.

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🔑 Takeaway: Inflammation doesn’t just signal with cytokines — it also stretches tissues. This stretch activates p53, which reshapes the immune response, especially in NK cells. Together they form a loop where mechanics and immunity reinforce one another in health and disease.

Cancer and The PEPCK Clutch!

Key Points

• Research suggests mediated mechanical stretch can mimic localized increases in blood pressure and inflammation, based on studies showing stretch affects vascular cells and induces inflammatory responses.

• It seems likely that PEPCK, an enzyme involved in metabolism, can be induced to support a metabolic cell state that promotes outcomes like prolonged cell life and disease, especially in cancer, where it supports cell survival under stress.

• The evidence leans toward mechanical stretch influencing cancer cell metabolism, potentially involving PEPCK, though direct links need further study.

Background

Mediated mechanical stretch refers to controlled mechanical forces applied to cells or tissues, often used in lab settings to simulate physiological conditions like increased blood pressure. This can affect how cells behave, particularly in blood vessels and potentially in cancer. PEPCK, or Phosphoenolpyruvate Carboxykinase, is an enzyme key to gluconeogenesis, the process of making glucose from non-carbohydrate sources, and is notably active in cancer cells under nutrient stress.

Connection to Blood Pressure and Inflammation

Studies show mechanical stretch can mimic conditions of high blood pressure and inflammation. For instance, stretch on vascular cells increases reactive oxygen species and inflammation markers, similar to what happens with hypertension (Mechanical stretch: physiological and pathological implications for human vascular endothelial cells). This suggests stretch can create a microenvironment akin to diseased states.

Role of PEPCK in Disease

PEPCK is crucial in cancer, where it helps cells survive by altering metabolism under stress, such as low glucose. Research indicates PEPCK supports cancer cell growth by enhancing glucose and glutamine use, potentially prolonging cell life and promoting disease progression (PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth).

Linking Mechanical Stretch and PEPCK

While direct studies linking mechanical stretch to PEPCK in cancer are limited, the connection seems plausible. Mechanical stretch can induce inflammation and metabolic changes, and in cancer, this could upregulate PEPCK, supporting a cell state that aligns with prolonged survival and disease promotion. This is an unexpected detail, as stretch is often seen as beneficial (e.g., exercise), but here it may exacerbate cancer conditions.

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Survey Note: Detailed Analysis of Mechanical Stretch, PEPCK, and Disease Promotion

This section provides a comprehensive exploration of the user's query, examining the potential for mediated mechanical stretch to mimic localized increases in blood pressure and inflammation, and whether PEPCK can be induced to support a metabolic cell state promoting outcomes that prolong cell life and promote disease. The analysis draws on various studies and blog posts referenced, ensuring a thorough understanding for readers with a scientific background.

Understanding Mediated Mechanical Stretch

Mediated mechanical stretch involves applying controlled mechanical forces to cells or tissues, often to simulate physiological or pathological conditions. Research indicates that such stretch can replicate the effects of increased blood pressure and inflammation at a localized level. For example, a study on vascular endothelial cells showed that mechanical stretch, especially under conditions mimicking hypertension, leads to the formation of reactive oxygen species and inflammation, aligning with pathological consequences (Mechanical stretch: physiological and pathological implications for human vascular endothelial cells). Another study, "The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression" (The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression), further supports that stretch can induce gene expression changes similar to those seen in high blood pressure, validating the user's premise.

Blood Pressure and Inflammation: Detailed Mechanisms

The connection between mechanical stretch and blood pressure is evident in studies showing stretch affects arterial stiffness and blood pressure regulation. For instance, regular stretching exercises have been shown to reduce blood pressure in hypertensive patients, suggesting a link between mechanical forces and vascular responses (Compliance of Static Stretching and the Effect on Blood Pressure and Arteriosclerosis Index in Hypertensive Patients). Inflammation is also induced by stretch, as seen in studies where cyclic mechanical stretch upregulates pro-inflammatory pathways, particularly in vascular smooth muscle cells, contributing to conditions like chronic venous insufficiency (The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression).

A detailed breakdown of relevant findings is presented in the following table, extracted from blog posts and studies:

Topic	Details	Exact Numbers	Relevant URLs
Mechanical Stretch	Causes sustained molecular signaling of pro-inflammatory and proliferative pathways, tied to p53, occurs in disturbed flow and undirected stretch at branch points and complex regions.	-	journals.physiology.org, blog.codondex.com
Blood Pressure	Meta-analysis of 7017 individuals identified 34 differentially expressed genes, 6 linked to BP and hypertension, MYADM (19q13) the only gene across diastolic, systolic BP, and hypertension.	7017, 34, 6	journals.plos.org, www.ncbi.nlm.nih.gov
Inflammation	Controlled by interaction between plasma membrane and submembrane at endothelial surface; MYADM knockdown induces inflammatory phenotype via ICAM-1 (19p13) increase, mediated by ERM actin cytoskeleton proteins; S1P2 (19p13) involved in immune, nervous, metabolic, cardiovascular, musculoskeletal, renal systems.	-	blog.codondex.com, www.ncbi.nlm.nih.gov, rupress.org, www.ncbi.nlm.nih.gov, www.jimmunol.org, www.ncbi.nlm.nih.gov, onlinelibrary.wiley.com, www.researchgate.net, www.ncbi.nlm.nih.gov, journals.asm.org, journals.plos.org, www.jbc.org, www.gastrojournal.org, www.spandidos-publications.com

This table highlights the molecular and physiological impacts, providing a foundation for understanding how stretch influences blood pressure and inflammation.

PEPCK and Its Role in Metabolic Cell States

PEPCK, or Phosphoenolpyruvate Carboxykinase, is a key enzyme in gluconeogenesis, converting oxaloacetate to phosphoenolpyruvate. Its role extends beyond normal physiology into cancer, where it supports metabolic flexibility under nutrient stress. Studies show PEPCK, particularly the mitochondrial isoform PCK2, is expressed in lung and other cancer tissues, aiding cell survival by enhancing glucose and glutamine utilization (PEPCK in cancer cell starvation). This metabolic adaptation can prolong cell life, especially in cancer, and promote disease progression by supporting tumor growth (PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth).

Linking Mechanical Stretch, PEPCK, and Disease Promotion

The user's query posits whether PEPCK can be induced to support a single metabolic cell state that promotes outcomes similar to those from mechanical stretch, which mimics increased blood pressure and inflammation, and whether this prolongs cell life and promotes disease. While direct studies linking mechanical stretch to PEPCK induction are scarce, indirect evidence suggests a connection. Mechanical stretch induces inflammation and alters glucose metabolism, as seen in skeletal muscle studies where stretch increases glucose uptake via ROS and AMPK pathways (Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase). In cancer, where inflammation is a known promoter, mechanical stretch could create a microenvironment that upregulates PEPCK, supporting a metabolic state conducive to prolonged cell survival and disease, particularly in tumors under stress.

For instance, a study on lung cancer progression under mechanical stretch highlights its role in tumor microenvironment changes, potentially affecting metabolic pathways (An Overview of the Role of Mechanical Stretching in the Progression of Lung Cancer). Given PEPCK's role in cancer metabolism, it's plausible that such conditions could induce PEPCK, aligning with the user's hypothesis. This is an unexpected detail, as stretch is often viewed positively (e.g., exercise benefits), but here it may exacerbate cancer by supporting a disease-promoting metabolic state.

Conclusion and Implications

Based on the analysis, it seems likely that mediated mechanical stretch, by mimicking localized increases in blood pressure and inflammation, can create conditions where PEPCK is induced to support a metabolic cell state. This state, particularly in cancer, can promote outcomes like prolonged cell life and disease progression, fitting the user's query. Further research is needed to confirm direct links, but the evidence leans toward this possibility, offering insights into how mechanical forces influence cancer metabolism.

Key Citations

• Mechanical stretch: physiological and pathological implications for human vascular endothelial cells

• The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression

• Compliance of Static Stretching and the Effect on Blood Pressure and Arteriosclerosis Index in Hypertensive Patients

• PEPCK in cancer cell starvation

• PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth

• Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase

• An Overview of the Role of Mechanical Stretching in the Progression of Lung Cancer

Electrons Rule Your Biology!

The mitochondrial Electron Transport Chain (ETC) is responsible for almost all cellular energy - ATP. One protein, GPD2 was adopted into the inner mitochondrial membrane, perhaps because it enabled ETC production to move to its electron processing limit. To do this, lipids are metabolized when cytoplasmic GPD1-DHAP convert Glycerol Kinase to G3P, which passes two additional electrons from the cytoplasm, through GPD2, to the internalized ETC complexes. 

When Mitochondrial Membrane Potential "Δψm" is within normal range, the GPD2 electrons enhance ATP energy production. When damage to lipids, fatty chains, cholesterols or other elements, constituting the inner mitochondrial membrane, disrupt Δψm the anchored ETC proteins can move fractionally apart causing electrons passing along the chain of ETC complexes to leak.

During disrupted Δψm the additional flow of GPD2 electrons can burden the ETC complexes, resulting in unstable molecules that contain oxygen and are highly reactive known as reactive oxygen species (ROS). Prolific ROS can increase CA+ levels, damage lipids in mitochondrial membranes, which can cause dysfunction and disease. In  a normal cellular environment this process can lead to ferroptosis, an iron-dependent form of cell death, induced by lipid peroxidation. 

A key bidirectional regulator of ferroptosis, p53 can adjust metabolism of iron, lipids, glutathione peroxidase 4, reactive oxygen species, and amino acids via a canonical pathway. GPD2 is transcribed by multiple factors that interact with p53 including Nrf2 and others during stress, but findings with E2F suggest a critical function controls a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation. 

P53 can also induce apoptosis through the mitochondrial pathway, contribute to necrosis by accumulating in the mitochondrial matrix and regulating autophagy. Mitochondrial p53 accumulation is an early event  not merely a consequence of apoptosis or a consequence of binding to damaged organelles in dying cells. Now, emerging evidence shows that ferroptosis plays a crucial role in tumor suppression via p53. 

Immune cells require massive energy boosts during synapse formation and lysis of a target cell when mitochondrial fitness is essential. However, tumor micro environments (TME's) alter lipid metabolism disrupting Δψm causing immune cells to function sub-optimally. Stimulation of T cells triggers a spike in cellular ATP production that doubles intracellular levels in <30 s and causes prolonged ATP release into the extracellular space. ATP release and autocrine feedback, via purinergic receptors collectively contribute to the influx of extracellular Ca2+ that is required for IL-2 production. The process has also been described for Natural Killer (NK) cells.

In the TME innate NK cells are dysfunctional due to lipid peroxidation inhibiting glucose metabolism. If innate immune cells are initially successful, adaptive immune responses may still fail because mitochondria reposition to the immune synapse where they transfer, including to immune cells, which can assist the target to evade immune response. Rapidly proliferating cancer cells may overwhelm initial immune responses and modify immune signaling promoting cancer and vascular remodeling.

ΔΨm as a measure of functional integrity maybe the flawed alert, a blind spot for of a cells' ADP-ATP pipeline. Likewise the status of TP53, from transcription through p53 isoform, may signal wide ranging affects of ΔΨm changes that incorporate fragmentation, accumulating damaged mitochondria, mitophagy, apoptosis or normal immune signaling and response through mitochondrial biogenesis, differentiation and angiogenesis. This modal duality aligns known functions of NK cells that under physiological conditions promote angiogenesis growth (as in Blastocyst implantation and placental vascularization) or NK's classic, cytolytic role in the innate immune response. 

Mitochondrial Phospholipid (MitoPLD), is anchored to the mitochondrial surface. It regulates mitochondrial shape, facilitating fusion and in the electron-dense nuage, of adjacent mitochondria, performs a critical piRNA generating function that is known to generate a spermatocyte-specific piRNA required for meiosis. piRNA are known to be aberrantly expressed in cancer cells.

Changes in mitochondrial membrane potential and ETC complexes can also influence piRNA-mediated control of transposable elements (TE's) through energy availability, ROS generation, and direct or indirect effects on piRNA biogenesis and function. piRNA restrain TE's that disrupt genes, chromosomal stability, damage DNA, cause inflammation, disease and/or cell death. For example, increased levels of endogenous retroviruses (ERV's), a TE subclass, trigger fibro inflammation and play a role in kidney disease development.

In mammals, the transcription of TEs is important for maintaining early embryonic development and related vital aspects of NK cell immune development. Intriguingly, regardless of the cell type, p53 sites are highly enriched in the endogenous retroviral elements of the ERV1 family. This highlights the importance of this repeat family in shaping the transcriptional network of p53 and its transcriptional role in interferon-mediated antiviral immunity. 

 

 

p53 Convergence and Immunity

Renewed interest in Bradykinin and its inactivation, by Angiotensin Converting Enzyme (ACE), during Covid infection reconfirmed RAS and KKS (Kallikrein-Kinin, Bradykinin) as the major systems of vasodilation and constriction contributing to blood pressure and disease. ACE2, a molecule of focus in Covid, reduces the Bradykinin product des-Arg9 bradykinin to inactive metabolites.

In pre-eclampsia reduced Kallikrein (KLK) generation and Bradykinin's activation, via its BK1 and BK2 receptor, modulates stress response through NF-κB and p53 pathways. These are the major cellular stress response pathways that promote or oppose apoptosis and influence cell fate. Two functionally divergent p53-responsive elements were discovered in the rat BK2 receptor promoter, which interact with ACE, play a significant role regulating vascular tone and blood pressure and in the cross-talk between RAS and KKS. 

In uterine immune cells RAS proteins AT1, AT2, and ANP are expressed and ANP co-localizes to uterine Natural Killer (uNK) cells between pregnancy day 10 and 12, immediately before spiral arterial modification. In mice this suggested that uNK contributes to the physiological changes in blood pressure between days 5 and 12.

During the first trimester the uNK cells dramatically increase, from around 15% to 70% of immune cells in the Decidua of the Uterus. Expressed RAS-KKS proteins during this time may be solely responsible for amplified stimulation of the plasma contact system at least via p53-mediated transcription and activation of the BK2 promoter.

In myocytes stretch-mediated release of angiotensin II (AngII) induced apoptosis by activating p53 that enhanced local RAS and decreased the Bcl-2-to-Bax protein ratio in the cell. In endothelial cells mechanical stretch interconnected innate and adaptive immune response in hypertension. This suggests that mechanical forces, such as those experienced in hypertension, can influence the immune system and contribute to inflammation, vascular damage associated with high blood pressure and vascular remodeling.

MYADAM and PRPF31 were the only genes from a meta-analysis that linked diastolic, systolic blood pressure and hypertension. These are located on Chromosome 19 between 50-55,000,000 bps, which includes all Killer immunoglobulin like receptors (KIR's), Kallikrein related peptidases (KLK's) and c19MC MiRNA's, in a region characterized by a 2X background deletion rate. During different trimesters it was found that NK cells, in pre-eclampsia, directly incorporate c19MC MiRNA's that are important to placental development and their deregulation could lead to the development of pre-eclampsia. 

It adds up that the massively disproportionate uNK activity in pregnancy and its impact on the mechanics of blood pressure could amplify sensitivities for p53 mediated stress response. It’s known that uNK cells contribute to the remodeling of spiral arteries and regulation of blood pressure, which are critical for fetal development. Similarly, on a cellular scale, abnormal cell growth and expansion of NK cells, may also amplify conditions that direct NK education and licensing to support growth, as in solid tumors and micro-vascular remodeling, or trigger inflammation, through cytokine expression and/or granulocyte killing of expanded missing-self cells. 

All Roads Lead to (Ch)Romosome 19!

A hepatocellular carcinoma (HCC) co-regulatory network exists between chromosome 19 microRNA cluster (C19MC) at 19q13.42, melanoma-A antigens, IFN-γ and p53, promoting an oncogenic role of C19MC that is disrupted by metal ions zinc and nickel. IFN-γ plays a co-operative role whereas IL-6 is antagonistic, each have a major bearing on the expression of HLA molecules on cancer cells. Analysis of Mesenchymal stem cells and cancer cells predicted C19MC modulation of apoptosis in induced pluripotency and tumorigenesis.

Key, differentially expressed genes in HCC included cancer-related transcription factors (TF) EGR1, FOS, and FOSB. From mRNA and miRNA expression profiles these were most enriched in the p53 signaling pathway where mRNA levels of each decreased in HCC tissues. In addition, mRNA levels of CCNB1, CCNB2, and CHEK1, key markers of the p53 signaling pathway, were all increased. miR-181a-5p regulated FOS and EGR1 to promote the invasion and progression of HCC by p53 signaling pathway and it plays an important role in maturation or impairment of natural killer (NK) cells.

A pan-cancer analysis, on microRNA-associated gene activation, produced the top 57 miRNAs that positively correlated with at least 100 genes. miR-150, at 19q13.33 was the most active, it positively correlated with 1009 different genes each covering at least 10 cancers. It is an important hematopoietic, especially B, T, and NK, cell specific miRNA.

Rapid functional impairment of NK cells following tumor entry limits anti-tumor immunity. Gene regulatory network analysis revealed downregulation of TF regulons, over pseudo-time, as NK cells transition to their impaired end state. These included AP-1 complex TF's, Fos, Fosb (19q13.32), Jun, Junb (19p13.13), which are activated during NK cell cytolytic programs and down regulated by interactions with inhibitory ligands. Other down-regulated TF's included Irf8, Klf2 (19p13.11), Myc, which support NK cell activation and proliferation. There were no significantly upregulated TF's suggesting that the tumor-retained NK state arises from the reduced activity of core transcription factors associated with promoting mature NK cell development and expansion.

Innate immune, intra-tumoral, stimulatory dendritic cells (SDCs) and NK cells cluster together and are necessary for enhanced T cell tumor responses. In human melanoma, SDC abundance is associated with intra-tumoral expression of the cytokine producing gene FLT3LG (19q13.33) that is predominantly produced by NK cells in tumors. Computed tomography exposes patients to ionizing X-irradiation. Determined trends in the expression of 24 radiation-responsive genes linked to cancer, in vivo, found that TP53 and FLT3LG expression increased linearly with CT dose. 

Undifferentiated embryonal sarcoma of the liver displays high aneuploidy with recurrent alterations of 19q13.4 that are uniformly associated with aberrantly high levels of transcriptional activity of C19MC microRNA. Further, TP53 mutation or loss was present with all samples that also display C19MC changes. The 19q13.4 locus is gene-poor with highly repetitive sequences. Given the noncoding nature and lack of an obvious oncogene, disruption of the nearby C19MC regulatory region became a target for tumorigenesis. 

The endogenous retroviral, hot-spot deletion rate at 19p13.11-19p13.12 and 19q33-19q42 occurs at double the background deletion rate. Clustered in and around these regions are many gene families including KIR, Siglec, Leukocyte immunoglobulin-like receptors and cytokines that associate important NK gene features to proximal NK genes that were overrepresented in a meta analysis of blood pressure. 

Endogenous retroviruses that invite p53 and its transcriptional network, at retroviral hot-spots, suggest that lymphocyte progenitors, such as ILC's and expanded, NK cells are synergistically responsive to transcription from this busy region including by the top differentially expressed blood pressure genes MYADM, GZMB, CD97, NKG7, CLC, PPP1R13L , GRAMD1A as well as (RAS-KKS) Kallikrein related peptidases to educate early and expanded NK cells that shape immune responses.  

p53 - Mediator Of Natural Killer Education

The regulation of rapidly transforming stem cells into trophoblasts and expanding embryonic cell phenotypes, between gestation day 8 and 15 is fast and furious. Research unraveling the finer detail points to the advent of pressure impacting evolving conditions for growth, transformation of cells, microvasculature and resulting tissue types. Notably, Natural Killer (NK) cells expand to around 30% of the cells in the stroma of the uterine wall. These uterine NK (uNK) cell subsets coexist alongside conventional NK cells. This unusual uNK quantitative imbalance motivated our research.   

uNK are closely associated with spiral artery remodeling, for placentation at the blastocyst implantation site. They possess a functional Renin- Angiotensin system (RAS), the cornerstones of blood pressure. The ratio of uNK cells expressing Angiotensin II receptor type 1 (AT1) markedly changed between gestation day 6 and 10. At day 10-12 Atrial Natriuretic Peptide, for vasoconstriction and dilation, strongly co-localized to uNK cells at the implantation sites. Expression of these vasoregulatory molecules by uNK suggests they contribute to the changes in blood pressure that occur between days 5 and 12 coincidental with their population explosion in the decidua during normal pregnancy.

Similar to Angiotensin, Bradykinin (BK) is produced from an inactive pre-protein kininogen that is activated by serine protease kallikrein (KLK), mostly represented on chromosome 19, where they associate with a number of other genes involved in blood pressure. Oakridge scientists predicted that BK induced a Covid19 "cytokine storm" that is responsible for disease progression. 

KLK's are located at 19q13.41, an active transposon region with a 2x background deletion rate clustered near Zinc Fingers and KIR's (Killer immunoglobulin like receptors) that inhibit NK cells.  A link was confirmed in mice uterine NK cells that regulated local tissue blood pressure, by at least AT1, partly in response to mechanical stretch of vasoconstriction and dilation induced by uterine NK's internal RAS. 

In reproduction, at  Chromosome 19 MiRNA Cluster (C19MC), 59 known miRNAs are highly expressed in human placentas and in the serum of pregnant women. Numerous C19MC miRNA's are also found in peripheral blood NK's and at least miR-517a-3p (a C19MC from fetal placenta) was incorporated into maternal NK cells in the third trimester, and was rapidly cleared after delivery. miRNA's also regulate the migration of human trophoblasts and suppress epithelial to mesenchymal transition (EMT) genes that are critical for maintaining the epithelial cytotrophoblast stem cell phenotype. 

In hepatocellular carcinoma (HCC) a co-regulatory network exists between C19MC miRNAs, melanoma-A antigens (MAGEAs), IFN-γ and p53 that promotes an oncogenic role of C19MC and is disrupted by metal ions zinc and nickel. IFN-γ plays a co-operative role whereas IL-6 plays an antagonistic role. Its an important immunoregulartory network, because, in the very least, IFN-γ and IL6 have a major baring on the expression of HLA/MHC molecules on cancer cells. 

Immediately adjacent to C19MC, is the leukocyte immunoglobulin-like receptor complex, from where LILRB1 receptor, also known as Mir-7, is expressed on NK cells. It binds MHC class I molecules, on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. LILRB1 has a polymorphic regulatory region that enhances transcription in NK Cells and recruits zinc finger protein YY1 that inhibits p53. It is required to educate expanded human NK cells and defines a unique antitumor NK cell subset with potent antibody-dependent cellular cytotoxicity.

In 2019 a study of arsenite-induced, human keratinocyte transformation demonstrated that knockdown of m6A methyltransferase (METTL3) significantly decreased m6A level, restored p53 activation and inhibited phenotypes in the-transformed cells. m6A downregulated expression of positive p53 regulator, PRDM2, through YTHDF2-promoted decay of mRNAs. m6A also upregulated expression of negative p53 regulator, YY1 and MDM2 through YTHDF1-stimulated translation of YY1 and MDM2 mRNA. Taken together, the study revealed the novel role of m6A in mediating human keratinocyte transformation by suppressing p53 activation and sheds light on the mechanisms of arsenic carcinogenesis via RNA epigenetics.

In 2021 a discovery that YTHDF2 is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. YTHDF2 maintains NK cell homeostasis and terminal maturation. It promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Analysis showed significant enrichment in cell cycle, division, including mitotic cytokinesis, chromosome segregation, spindle, nucleosome, midbody, and chromosome. This data supports roles of YTHDF2 in regulating NK proliferation, survival, and effector functions. 

As part of the 2021 discovery, transcriptome-wide screening identified TDP-43 to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons. Growth of the developing cerebral cortex is controlled by Mir-7 through the p53 Pathway

Here we have broadly described mechanisms by which NK cells maintain tissue homeostasis where tightly regulated p53 optimizes cellular conditions to 'self' educate the expanded NK cells. Those that express NKG2A and/or one or several KIRs, for which cognate ligands are present, become educated and as such transform to potent killers in response to their missing-self. Therefore, p53 isoforms have the innate capacity to promote a cellular homeostasis that makes it the mediator for optimal education of expanded NK cells.