mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-4-789-796mimmun-1884Research ArticleКРАТКИЕ СООБЩЕНИЯSHORT COMMUNICATIONSВЛИЯНИЕ ТЕРАПИИ НА ЛПС-ИНДУЦИРОВАННУЮ СЕКРЕЦИЮ ЦИТОКИНОВ КЛЕТКАМИ ВРОЖДЕННОГО ИММУНИТЕТА КРОВИ ПАЦИЕНТОВ С БРОНХИАЛЬНОЙ АСТМОЙINFLUENCE OF THERAPY UPON LPS-INDUCED CYTOKINE SECRETION BY THE BLOOD-DERIVED INNATE IMMUNITY CELLS OF THE BRONCHIAL ASTHMA PATIENTSСеровД. А.SerovD. A.

младший научный сотрудник лаборатории молекулярной биомедицины

142290, Россия, Московская обл., г. Пущино, ул. Институтская, 2

Тел.: 8 (985) 319-03-21.Факс: 8 (4967) 33-05-32

Junior Research Associate, Laboratory Molecular Biomedicine

142290, Russian Federation, Moscow Region, Pushchino, Institutskaya str., 2

Phone: 7 (985) 319-03-21Fax: 7 (4967) 33-05-32

dmitriy_serov_91@mail.ruКабановД. С.KabanovD. S.

к.б.н., старший научный сотрудник лаборатории молекулярной биомедицины

г. Пущино, Московская обл.

PhD (Biology), Senior Research Associate, Laboratory of Molecular Biomedicine

Pushchino, Moscow Region

КосяковаН. И.KosyakovaN. I.

д.м.н., заведующий отделением иммунологии-аллергологии

г. Пущино, Московская обл.

PhD, MD (Medicine), Head, Department of Immunology/Allergology

Pushchino, Moscow Region

ПрохоренкоИ. Р.ProkhorenkoI. R.

д.б.н., главный научный сотрудник лаборатории молекулярной биомедицины

г. Пущино, Московская обл.

PhD, MD (Biology), Main Research Associate, Laboratory of Molecular Biomedicine

Pushchino, Moscow Region

ФГБУН «Институт фундаментальных проблем биологии РАН»РоссияInstitute of Fundamental Problems of Biology, Russian Academy of SciencesRussian FederationФГАУЗ «Больница Пущинского научного центра РАН»РоссияClinical Hospital at the Pushchino Research CenterRussian Federation201929102019214препринт789796Copyright © Серов Д.А., Кабанов Д.С., Косякова Н.И., Прохоренко И.Р., 20192019Серов Д.А., Кабанов Д.С., Косякова Н.И., Прохоренко И.Р.Serov D.A., Kabanov D.S., Kosyakova N.I., Prokhorenko I.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1884

Среди хронических воспалительных заболеваний респираторного тракта бронхиальная астма (БА) является одним из самых распространенных в мире. Поскольку БА индуцирует системный воспалительный процесс, необходимо всестороннее исследование влияния этого заболевания и его терапии на функциональное состояние организма и иммунной системы крови в частности. В фазе обострения БА клетки респираторного тракта пациентов могут усиливать секрецию не только провоспалительных, но и противовоспалительных медиаторов, последние из которых способны подавлять активность клеток иммунной системы крови. В настоящей работе была проведена оценка влияния терапии БА на выраженность воспаления и функциональное состояние клеток иммунитета периферической крови. Тестом функциональной активности иммунных клеток крови служила липополисахарид (ЛПС)-индуцированная секреция цитокинов ex vivo. ЛПС является классическим провоспалительным агентом бактериальной природы. Нами исследованы ответы клеток крови пациентов с верифицированным диагнозом БА до начала лечения и через две недели базисной противовоспалительной терапии. По клиническим показателям пациентам была назначена терапия комбинацией ингаляционных глюкокортикостероидов и агонистов β-адренорецепторов или антилейкотриеновый препарат (монтелукаст). Параллельно были исследованы ответы клеток крови условно здоровых добровольцев на ЛПС. Секрецию TNFα, IL-6, IL-8 клетками крови оценивали после экспозиции с ЛПС (100 нг/мл) в течение 6 ч, IFNγ, IL-17A, IL-1β – 24 ч. Параллельно оценивали секрецию цитокинов клетками крови, не стимулированными ЛПС. Проведен контроль уровней IL-4 в плазме крови пациентов и условно здоровых добровольцев. Концентрации цитокинов определяли методом ИФА. Показано, что через две недели терапии у пациентов уменьшалась фоновая секреция IL-6 клетками крови, что может указывать на снижение выраженности воспаления. Терапия не оказывала влияния на фоновую и ЛПС-индуцированную секрецию IL-1β, IL-1ra, IFNγ и IL-8 клетками пациентов с БА. В течение 2-недельной терапии концентрация IL-4 в плазме крови пациентов не изменялась. Клетки крови пациентов с БА секретировали значительно меньше TNFα и IL-8 в контроле и после стимуляции ЛПС, чем клетки условно здоровых добровольцев, что подтверждает предположение о частичном угнетении активности иммунных клеток крови при БА. Через две недели терапии наблюдалось увеличение ЛПС-индуцированной секреции TNFα клетками крови пациентов. С целью  определения механизма усиления ЛПС-индуцированной секреции TNFα была оценена фоновая секреция растворимой формы рецептора CD14 (sCD14) в крови пациентов с БА до терапии и через две недели послетерапии. Показано, что после терапии БА в крови пациентов не происходит увеличения концентрации sCD14. Полученные результаты указывают на sCD14-независимый механизм усиления ЛПС-индуцированной секреции TNFα. Базисная противовоспалительная терапия не только снижает концентрацию IL-6 в крови, но частично восстанавливает активность клеток врожденного иммунитета крови пациентов с БА.

Bronchial asthma (BA) is the most widespread chronic inflammatory disease. Since BA is associated with a systemic inflammation state, a comprehensive study of its effect in this disease, and influence of pathogenetic therapy should be performed, by studying the whole blood cytokine status of the patients suffering with BA. The cells from respiratory tract in acute-phase BA patients may produce pro-, as well as anti-inflammatory mediators. The anti-inflammatory mediators are able to suppress activity of immune cells in peripheral blood. Thus, the aim of present study was to evaluate eventual inflammation-associated and functional activity of immune cells from the patients’ peripheral blood in BA and following appropriate therapy. Bacterial lipopolysaccharide (LPS) a classical pro-inflammatory agent. We have studied an LPSinduced cytokine-induced ex vivo secretion model by peripheral blood immune cells, as a relevant test for their functional activity. The LPS-induced responses of whole blood cells from patients with proven BA diagnosis have been studied at pre-treatment time points, and following two weeks of basic anti-inflammatory therapy. According to clinical indications, the antagonists of CysLTR1, or combinations of glucocorticosteroids and β-adrenoreceptor agonists were administered by inhalation to BA patients. LPS-induced production of TNFα, IL-6, IL-8 (at 6 h) and IFNγ, IL-17A or IL-1β (at 24 h) by whole blood cells from BA patients or healthy volunteers has been assessed by ELISA technique. The cytokine production from non-stimulated whole blood cells from BA patients and healthy volunteers were used as the baseline control. IL-4 concentrations in plasma of BA patients and healthy volunteers were also measured. We have shown a decrease of IL-6 production in control blood samples from BA patients after two weeks of therapy. This may indicate the attenuation of the observed inflammatory process. The therapy applied did not influence the background levels and LPS-induced secretion of IL-1β, IL-1ra, IFNγ, and IL-8 in whole blood samples from BA patients. IL-4 plasma levels in BA patients were not changed after two weeks of therapy. It has been shown that whole blood from BA patients produced less TNFα and IL-8, both in control samples, and during their response to LPS, than the values obtained in healthy volunteers. These findings are in agreement with a notion that BA causes partial depression of innate immune cells activity. The increased LPS-induced TNFα secretion by the whole blood cells from BA patients has been observed following two weeks of basic anti-inflammatory therapy. We suggest that the increased LPS-induced TNFα secretion could be explained by partial restoration of peripheral blood immune cell activity associated with anti-inflammatory BA therapy. To elucidate the mechanism of increased LPS-induced TNFα secretion, we have estimated whole blood concentration of soluble CD14 (sCD14) in BA patients. No significant differences between sCD14 concentrations have been found. Obtained result presume existence of sCD14-independent mechanism of TNFα regulation by whole blood cells in response on LPS which may occur during anti-inflammatory therapy of BA. We suppose that basic anti-inflammatory therapy of BA does not simply reduce IL-6 concentration in peripheral blood, but may also partially restore the activity of innate immune cells in BA patients.

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