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Modulation of Inflammatory Cytokine Production in Human Monocytes by cGMP and IRAK3

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posted on 23.06.2022, 03:41 authored by TH Nguyen, Anna Maree AxellAnna Maree Axell, Ilona Turek, B Wright, Terri Meehan-AndrewsTerri Meehan-Andrews, Helen IrvingHelen Irving
Interleukin-1 receptor-associated kinase-3 (IRAK3) is a critical checkpoint molecule of inflammatory responses in the innate immune system. The pseudokinase domain of IRAK3 contains a guanylate cyclase (GC) centre that generates small amounts of cyclic guanosine monophosphate (cGMP) associated with IRAK3 functions in inflammation. However, the mechanisms of IRAK3 actions are poorly understood. The effects of low cGMP levels on inflammation are unknown, there-fore a dose–response effect of cGMP on inflammatory markers was assessed in THP-1 monocytes challenged with lipopolysaccharide (LPS). Sub-nanomolar concentrations of membrane permeable 8-Br-cGMP reduced LPS-induced NFκB activity, IL-6 and TNF-α cytokine levels. Pharmacologically upregulating cellular cGMP levels using a nitric oxide donor reduced cytokine secretion. Downregu-lating cellular cGMP using a soluble GC inhibitor increased cytokine levels. Knocking down IRAK3 in THP-1 cells revealed that unlike the wild type cells, 8-Br-cGMP did not suppress inflammatory responses. Complementation of IRAK3 knockdown cells with wild type IRAK3 suppressed cytokine production while complementation with an IRAK3 mutant at GC centre only partially restored this function. Together these findings indicate low levels of cGMP form a critical component in suppressing cytokine production and in mediating IRAK3 action, and this may be via a cGMP enriched nanodomain formed by IRAK3 itself.

Funding

This work was sponsored by the United States Army Research Office and was accomplished under Grant Numbers W911NF-17-1-0303 and W911NF-19-1-0435. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Office or the U.S. Government. The U.S. Government is authorised to reproduce and distribute reprints for government purposes notwithstanding any copyright notation herein.

History

Publication Date

01/03/2022

Journal

International Journal of Molecular Sciences

Volume

23

Issue

5

Article Number

ARTN 2552

Pagination

18p.

Publisher

MDPI

ISSN

1661-6596

Rights Statement

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.