Инетерейкин-37 и Инетерейкин-38
Два представителя семейства IL-37 и IL-38 пока что не имеют определенного и общепризнанного значения. Открытые впервые in silico в начале 2000-ых, эти цитокины только недавно начали открывать нам свои функции.
Интерлейкин-37 это единственный представитель семейства, не имеющий аналога у мышей. У этого цитокина существует множество сплайс-изоформ, но самой распространённой и изученной является IL-37b. Для этого цитокина была показана возможность расщепления in vitro каспазой-1, однако сайт расщепления отличается от канонического сайта каспазы-1 в молекулах остальных представителей семейства интерлейкина-1. [43] Исследования показали, что IL-37b способен связываться с рецептором IL-18 и IL-18BP, однако, это связывание имеет очень низкую аффинность и IL-37 не проявляет ни антагонистической ни агонистической активности на IL-18. [65] При этом, клетки, трансфецированные геном IL-37 под мощным промотором, обнаруживали более слабый ответ на индукторы TIR-сигнальной трансдукции: провоспалительные цитокины и PAMPs. IL-37 может оказаться внутриклеточным негативным регулятором иммунитета. [78] IL-37b имеет ядерную локализацию, причем в отличие от IL-1α и IL-33 пропептидным фрагментом. Также показано прямое взаимодействие IL-37 с сигнальной молекулой касказа рецептора TGF-β – SMAD3. [32] Может оказаться, что IL-37 – это фактор модулирующий ответ на уровне транскрипционной активности генов.
Интерлейкин-38 – это последний на данный момент, одиннадцатый член семейства интерлейкина-1. IL-38 имеет высокое сходство аминокислотной последовательности с IL-36Ra (46%) и IL-1Ra (41%), [46]. По всей видимости, IL-38 делит специфический рецептор с IL-36, имеет сравнимую с IL-36Ra аффинность связывания. Этот цитокин подавляет продукцию IL-17 и IL-22 T-лимфоцитами, подавляет выработку IL-8 другими отвечающими на IL-36γ клетками. Анализ паттерна экспрессии гена IL-38 - IL1F11 показал его высокое присутствие в коже и B-клетках миндалин. [87] По совокупности этих данных сейчас можно считать IL-38 специфическим рецепторным антагонистом IL-36, аналогичным IL-36Ra, пока, однако, не ясным остается его дублирующее значение.
Заключение
Семейство цитокинов интерлейкина-1 как видно из приведенного выше анализа является очень разнообразным семейством взаимосвязанных сигнальных молекул. Плейотропные свойства, наличие дублеров и рецепторных антагонистов делает это семейство очень интересным с точки зрения системной биологии и нейроиммуноэндокринологии. Большое количество патологий, опосредованных дисрегуляцией представителей этой группы в системе цитокинов создает обширные возможности для обнаружения в нем перспективных молекулярных фармакологических мишеней.
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