IL-13 but not IL-4 signaling via IL-4Rα protects mice from papilloma formation during DMBA/TPA two-step skin carcinogenesis

Interleukin 4 (IL-4) was shown to be tumor-promoting in full carcinogenesis studies using 3-methylcholanthrene (MCA). Because heretofore the role of IL-4 in DMBA/TPA (9,10-dimethyl-1,2-benz-anthracene/12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis was not studied, we performed such experiments using either IL-4(-/-) or IL-4R{alpha}(-/-) mice. We found that IL-4R{alpha}(-/-) but not IL-4(-/-) mice have enhanced papilloma formation, suggesting that IL-13 may be involved. Indeed, IL-13(-/-) mice developed more papillomas after exposure to DMBA/TPA than their heterozygous IL-13-competent littermate controls. However, when tested in a full carcinogenesis experiment, exposure of mice to 25 {My}g of MCA, both IL-13(-/-) and IL-13(+/-) mice led to the same incidence of tumors. While IL-4 enhances MCA carcinogenesis, it does not play a measurable role in our DMBA/TPA carcinogenesis experiments. Conversely, IL-13 does not affect MCA carcinogenesis but protects mice from DMBA/TPA carcinogenesis. One possible explanation is that IL-4 and IL-13, although they share a common IL-4R{alpha} chain, regulate signaling in target cells differently by employing distinct JAK/STAT-mediated signaling pathways downstream of IL-13 or IL-4 receptor complexes, resulting in different inflammatory transcriptional programs. Taken together, our results indicate that the course of DMBA/TPA- and MCA-induced carcinogenesis is affected differently by IL-4 versus IL-13-mediated inflammatory cascades

Covid-19 therapy: From myths to reality and hopes

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, is unprecedented for the 21st century and has already affected countries with a total population of billions of people. The number of infected has already surpassed 30 million people and the number of deaths has exceeded 1 million. Unfor-tunately, Russia is still one of the five countries with the largest number of infected people, although mortality from COVID-19 is significantly lower than in many other countries. Since the virus and the pathogenesis caused by it have a lot of new and unexpected features, high-tech and specific anti-viral drugs and vaccines have not yet been created. The most promising targets for future drug development are enzymes necessary for the life cycle of this particular virus (such as components of the replicase complex or viral proteases). Unexpected circumstances are pushing the evaluation of a number of previously developed and existing drugs directed toward other RNA viruses, some of which have already been shown effective in clinical trials against SARS-CoV-2. There is no doubt that soon prototypes of drugs of this class with higher specificity and effective-ness will be found. Another group of potential drugs are known drugs that are directed against various aspects of the pathogenesis caused by SARS-CoV-2, in particular, cytokine storm or coagulopathy. It should be emphasized that the genome of the virus encodes about 10 additional proteins, some of which may be related to unusual aspects of pathogenesis during COVID-19. Basic research should determine which of these proteins can be targets for specific therapy. Finally, the fact that neutralizing antibodies are found in the blood plasma of many patients and can be used for the prevention and treatment of COVID-19, indicates the potential of using recombinant neutralizing antibodies as drugs, and secondly, confirms the possibility of creating effective vaccines. This mini-review discusses therapeutic approaches and the status of clinical trials using drugs that already existed before the pandemic and were originally developed against other infectious agents or for the treatment of autoimmune pathologies. These drugs are part of today's arsenal in therapeutic protocols and are used in an attempt to cope with the COVID-19 epidemic in different countries. © 2020 Russian Association of Allergologists and Clinical Immunologists, St. Petersburg Regional Branch (SPb RAACI). All rights reserved