When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the initiation and/or to the progression of atherosclerosis, tumors or pulmonary hypertension; diseases that are decisively furthered by the presence of oxidizing agents. Redox sensitive genes, like the zinc finger transcription factor early growth response 1 (Egr-1), play a pivotal role in the pathophysiology of these diseases. Apart from inducing apoptosis, signaling partners like the MEK/ERK pathway or the protein kinase C (PKC) can activate salvage programs such as cell proliferation that do not ameliorate, but rather worsen their outcome. Here, we review the currently available data on Egr-1 related signal transduction cascades in response to oxidative stress in the progression of epidemiologically significant diseases. Knowing the molecular pathways behind the pathology will greatly enhance our ability to identify possible targets for the development of new therapeutic strategies.

Antarctica challenges human explorers by its extreme environment. The effects of these unique conditions on the human physiology need to be understood to best mitigate health problems in Antarctic expedition crews. Moreover, Antarctica is an adequate Earth-bound analogue for long-term space missions. To date, its effects on human physiology have been studied mainly in male cohorts though more female expeditioners and applicants in astronaut training programs are selected. Therefore, the identification of sex differences in stress and immune reactions are becoming an even more essential aim to provide a more individualized risk management. Ten female and 16 male subjects participated in three 1-year expeditions to the German Antarctic Research Station Neumayer III. Blood, saliva, and urine samples were taken 1–2 months prior to departure, subsequently every month during their expedition, and 3–4 months after return from Antarctica. Analyses included cortisol, catecholamine and endocannabinoid measurements; psychological evaluation; differential blood count; and recall antigen- and mitogen-stimulated cytokine profiles. Cortisol showed significantly higher concentrations in females than males during winter whereas no enhanced psychological stress was detected in both sexes. Catecholamine excretion was higher in males than females but never showed significant increases compared to baseline. Endocannabinoids and N-acylethanolamides increased significantly in both sexes and stayed consistently elevated during the confinement. Cytokine profiles after in vitro stimulation revealed no sex differences but resulted in significant time-dependent changes. Hemoglobin and hematocrit were significantly higher in males than females, and hemoglobin increased significantly in both sexes compared to baseline. Platelet counts were significantly higher in females than males. Leukocytes and granulocyte concentrations increased during confinement with a dip for both sexes in winter whereas lymphocytes were significantly elevated in both sexes during the confinement. The extreme environment of Antarctica seems to trigger some distinct stress and immune responses but—with the exception of cortisol and blood cell counts—without any major relevant sex-specific differences. Stated sex differences were shown to be independent of enhanced psychological stress and seem to be related to the environmental conditions. However, sources and consequences of these sex differences have to be further elucidated.

Based on previous findings that early growth response 1 (Egr-1) participates in leukocyte recruitment and cell proliferation in vitro, this study was designed to investigate its mode of action during arteriogenesis in vivo. In a model of peripheral arteriogenesis, Egr-1 was significantly upregulated in growing collaterals of wild-type (WT) mice, both on mRNA and protein level. Egr-1^−/− mice demonstrated delayed arteriogenesis after femoral artery ligation. They further showed increased levels of monocytes and granulocytes in the circulation, but reduced levels in adductor muscles under baseline conditions. After femoral artery ligation, elevated numbers of macrophages were detected in the perivascular zone of collaterals in Egr-1^−/− mice and mRNA of leukocyte recruitment mediators was upregulated. Other Egr family members (Egr-2 to -4) were significantly upregulated only in Egr-1^−/− mice, suggesting a mechanism of counterbalancing Egr-1 deficiency. Moreover, splicing factor-1, downregulated in WT mice after femoral artery ligation in the process of increased vascular cell proliferation, was upregulated in Egr-1^−/− mice. αSM-actin on the other hand, significantly downregulated in WT mice, showed no differential expression in Egr-1^−/− mice. While cell cycle regulator cyclin E and cdc20 were upregulated in Egr-1^−/− mice, cyclin D1 expression decreased below the detection limit in collaterals, and the proliferation marker ki67 was not differentially expressed. In conclusion, compensation for deficiency in Egr-1 function in leukocyte recruitment can presumably be mediated by other transcription factors; however, Egr-1 is indispensable for effective vascular cell cycle progression in arteriogenesis.

The zinc finger transcription factor Egr-1 (Early growth response 1) is central to several growth factors and represents an important activator of target genes not only involved in physiological processes like embryogenesis and neonatal development, but also in a variety of pathophysiological processes, for example atherosclerosis or cancer. Current options to investigate its transcription and activation in vivo are end-point measurements that do not provide insights into dynamic changes in the living organism.

A prolonged stress burden is known to hamper the efficiency of both the innate and the adaptive immune systems and to attenuate the stress responses by the catecholaminergic and endocannabinoid (EC) systems. Key mechanisms of innate immunity are the eradication of pathogens through phagocytosis and the respiratory burst. We tested the concentration-dependent, spontaneous and stimulated (via TNFα and N-formylmethionine-leucyl-phenylalanine) release of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) in vitro in response to norepinephrine (NE) and AM1241, a pharmacological ligand for the EC receptor CB₂. We evaluated phagocytosis of Dectin-1 ligating zymosan particles and tested the cytokine response against Candida antigen in an in vitro cytokine release assay. Increasing concentrations of NE did not affect phagocytosis, yet stimulated ROS release was attenuated gradually reaching maximum suppression at 500 nM. Adrenergic receptor (AR) mechanisms using non-AR-selective (labetalol) as well as specific α-(prazosin) and β-(propranolol) receptor antagonists were tested. Results show that only labetalol and propranolol were able to recuperate cytotoxicity in the presence of NE, evidencing a β-receptor-mediated effect. The CB₂ agonist, AM1241, inhibited phagocytosis at 10 µM and spontaneous peroxide release by PMNs. Use of the inverse CB₂ receptor agonist SR144528 led to partial recuperation of ROS production, confirming the functional role of CB₂. Additionally, AM1241 delayed early activation of monocytes and induced suppression of IL-2 and IL-6 levels in response to Candida via lower activity of mammalian target of rapamycin (mTOR). These findings provide new insights into key mechanisms of innate immunity under stressful conditions where ligands to the sympatho-adrenergic and EC system are released.