Abdominal aortic aneurysm (AAA) is a prevalent life-threatening disease, where aortic wall degradation is mediated by accumulated immune cells. Although cytokines regulate inflammation within the aorta, their contribution to AAA via distant alterations, particularly in the control of hematopoietic stem cell (HSC) differentiation, remains poorly defined. Here we report a pathogenic role for the interleukin-27 receptor (IL-27R) in AAA, as genetic ablation of IL-27R protects mice from the disease development. Mitigation of AAA is associated with a blunted accumulation of myeloid cells in the aorta due to the attenuation of Angiotensin II (Ang II)-induced HSC expansion. IL-27R signaling is required to induce transcriptional programming to overcome HSC quiescence and increase differentiation and output of mature myeloid cells in response to stress stimuli to promote their accumulation in the diseased aorta. Overall, our studies illuminate how a prominent vascular disease can be distantly driven by a cytokine-dependent regulation of bone marrow precursors.

Acute myeloid leukemia (AML) is an aggressive malignancy that requires rapid treatment with chemotherapies to reduce tumor burden. However, these chemotherapies can compromise lymphocyte function, thereby hindering normal anti-tumor immune responses and likely limiting the efficacy of subsequent immunotherapy. To better understand these negative impacts, we assessed the immunological effects of standard-of-care AML therapies on lymphocyte phenotype and function over time. When compared to healthy donors, untreated AML patients showed evidence of lymphocyte activation and exhaustion and had more prevalent CD57+NKG2C+ adaptive NK cells, which was independent of human cytomegalovirus (HCMV) status. HMA/venetoclax treatment resulted in a greater fraction of T cells with effector memory phenotype, inhibited IFN-γ secretion by CD8+ T cells, upregulated perforin expression in NK cells, downregulated PD-1 and 2B4 expression on CD4+ T cells, and stimulated Treg proliferation and CTLA-4 expression. Additionally, we showed increased expression of perforin and CD39 and enhanced IFN-γ production by T cells from pre-treatment blood samples of venetoclax-resistant AML patients. Our results provide insight into the lymphocyte status in previously untreated AML patients and the effects of standard-of-care treatments on their biology and functions. We also found novel pre-treatment characteristics of T cells that could potentially predict venetoclax resistance.

Primary pancreatic injury that occurs in acute pancreatitis leads to necrosis of pancreatic cells and is accompanied by the development systemic inflammatory response of varying severity. Systemic inflammatory response, in turn, can lead to the development of multiple organ dysfunction syndrome and death of patients. The release of damage-associated molecular patterns into the extracellular space is the trigger pathological mechanism underlying these processes. The released patterns exert their effects via Toll-like receptors (TLR). These findings suggest that TLR can be considered a new target for therapeutic intervention in acute pancreatitis. We studied mRNA expression of TLR2 and TLR4 in the peripheral blood mononuclear cells from the patients with acute pancreatitis and showed a decrease in the examined parameters associated with lornoxicam treatment. Anti-mediator therapy decreased mortality in these patients.

The use of lornoxicam at the onset of acute pancreatitis decreased TLR2 and TLR4 expression and the production of proinflammatory cytokines, thereby reducing the risk of systemic complications and mortality.

In this review we cover key issues, concerned with the effects of cytokines in cardiac tissue and cardiac cells. We discuss the effects of proinflammatory cytokines under non-pathological conditions and their mechanisms dependent and independent of nitric oxide. The role of proinflammatory cytokines is considered in acute myocardial infarction and in heart failure. We also describe proinflammatory cytokines as inductors of arrhythmia. We discuss ionic current alternation as possible mechanisms of cytokines action in heart. We consider TNF-α as a possible player in this signaling cascade. It was shown that TNF-α induced alternation of transmembrane action potentials. Influence of TNF-α on transient outward current (I to ), I Kur , I Kr , I Ks , I K1 is also reported. We discuss the interplay between TNF-α and Ca 2+ current, influence of TNF-α on SERCA. Then we consider influence of IL-1 on action potentials, I Na , I Ca , I K . We also address the role of IL-2, IL-6, and IL-11. Finally using TNF-α and IL-6 as an example we discuss the effects of cytokines on mechanoelectrical feedback. Perfusion of cardiac tissue with TNF-α containing solution leads to abnormalities in cardiac electrical activity, majorly to prolongation of APD90 and appearance of hump-like depolarization at APD90 level. After reaching E c hump-like depolarization transforms into extra-AP, leading to sustained arrhythmias. TNF-α activates NO cardiomyocyte synthases and the rise of intracellular NO levels opens MGCs, which leads to sodium entry into the cell, which depolarizes cellular membrane, shifting resting potential towards E C . We proposed and proved that TNF-α triggered arrhythmias can be mediated through activation of MGCs. Stretching of preparations removed TNF-α. Perfusion of preparation with IL-6 containing solution leads to fibrillation in response to low levels of stretch. IL-6 mechanisms of action are mediated by NO synthases A. Kamkin (B)

Резюме. В настоящее время в литературе активно обсуждается неоднозначная роль распознаю-щих рецепторов врожденного иммунитета, в частности TLRs, в иммунопатогенезе бронхиальной астмы (БА).Цель нашей работы -исследование экспрессии ТLR2 и TLR4 на уровне клеток слизистой полости носа и лейкоцитов периферической крови (ЛПК) больных БА разной степени тяжести.В исследование были включены 40 детей с БА (3-12 лет) и 10 здоровых детей того же возраста. Методом ПЦР-РВ оценивали экспрессию генов TLR2 и TLR4 в соскобах со слизистой полости носа и в ЛПК; методом проточной цитометрии определяли процент моноцитов, лимфоцитов и гранулоци-тов, экспрессирующих TLR2 TLR4, и интенсивность их экспрессии; методом мультиплексного им-мунофлуоресцентного анализа оценивали уровень про-и противовоспалительных цитокинов (IL-1β, IL-1ra, IL-6, IL-8, IL-10, TNFα) в назальных смывах.В результате проведенного исследования выявлена гиперактивация факторов врожденного имму-нитета на уровне слизистой оболочки полости носа у больных с БА, проявляющаяся повышением экспрессии генов TLR2, TLR4 и выработки как провоспалительных, так и противовоспалительных цитокинов. Выявлена связь между уровнем цитокинов и степенью тяжести бронхиальной астмы. В периферической крови определено достоверное увеличение экспрессии TLR2 и TLR4 на циркули-рующих CD14 + моноцитах у детей с БА. Таким образом, показано увеличение экспрессии генов TLRs слизистой полости носа и повыше-ние поверхностной экспрессии TLR2 и TLR4 на циркулирующих моноцитах больных бронхиальной астмой по сравнению со здоровыми детьми. Выявленные изменения свидетельствуют о вовлечении системы TLRs в иммунопатогенез бронхиальной астмы. В дальнейшем TLRs могут быть использова-ны в качестве маркеров прогноза течения БА и возможных терапевтических мишеней.

The production of TNF-alpha and IFN-alpha cytokines by peripheral blood mononuclears in response to stimulation by TLR2/6, TLR4, TLR5, TLR9 ligands (zymosan, LPS, flagellin, and CpG-oligodeoxynucleotide, respectively) was studied in donors and patients with common variable immunodeficiency. Individual characteristics of TNF-alpha production by mononuclears were revealed in donors. Reduced stimulated production of TNF-alpha in response to stimulation with TLR4 and TLR5 ligands in vitro was detected in patients with common variable immunodeficiency.

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