Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis

Abstract

Background IRAK3 is a critical modulator of inflammation in innate immunity. IRAK3 is associated with many inflammatory diseases, including sepsis, and is required in endotoxin tolerance to maintain homeostasis of inflammation. The impact of IRAK3 on inflammatory markers such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cell culture models remains controversial. Objective To analyse temporal effects of IRAK3 on inflammatory markers after one- or two-challenge interventions in cell culture models. Methods A systematic search was performed to identify in vitro cell studies reporting outcome measures of expression of IRAK3 and inflammatory markers. Meta-analyses were performed where sufficient data were available. Comparisons of outcome measures were performed between different cell lines and human and mouse primary cells. Results The literature search identified 7766 studies for screening. After screening titles, abstracts and full-texts, a total of 89 studies were included in the systematic review. Conclusions The review identifies significant effects of IRAK3 on decreasing NF-κB DNA binding activity in cell lines, TNF-α protein level at intermediate time intervals (4h–15h) in cell lines or at long term intervals (16h–48h) in mouse primary cells following one-challenge. The patterns of TNF-α protein expression in human cell lines and human primary cells in response to one-challenge are more similar than in mouse primary cells. Meta-analyses confirm a negative correlation between IRAK3 and inflammatory cytokine (IL-6 and TNF-α) expression after two-challenges.

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

“…Treatment with LPS markedly stimulated production of TNF-α and IL-6 cytokines in K5-1 IRAK3 +/− or K6-3 IRAK3 −/− monocytes compared with wild type monocytes ( Figure 4 C,E and Supplemental Figure S7B,D ), confirming the suppressive effects of IRAK3 on inflammatory responses to endotoxins reported previously [ 3 , 4 , 10 , 11 , 46 ]. To determine if cGMP could reduce LPS-induced cytokine production, the K6-3 IRAK3 −/− cells were simultaneously exposed to LPS and 8-Br-cGMP, and no change in TNF-α and IL-6 protein levels were seen ( Figure 4 D,F).…”

“…To study how different domains of IRAK3 influence its effects on production of inflammatory cytokines, the knockdown cell lines were complemented with wild type and mutant versions of IRAK3 protein ( Figure 5 A). K6-3 IRAK3 −/− or K5-1 IRAK3 +/− cells transfected with IRAK3 wild type exhibited significant decreases in LPS-induced IL-6 and TNF-α protein levels compared to the level of untransfected cells ( Figure 5 B,C and Supplemental Figure S9 ), further confirming IRAK3 inhibits inflammatory responses [ 3 , 10 , 11 ]. The IRAK3 R372L mutant decreases GC activity and fails to reduce LPS-induced NFκB activity [ 14 ].…”

“…IRAK3 downregulates the signal cascade by inhibiting the dissociation of IRAK-TRAF6 from the receptor–myddosome complex [ 3 , 10 ]. The suppressive effect of IRAK3 on inflammatory responses via NFκB activation pathway (or other pathways such as inhibiting translational control of pro-inflammatory cytokines) subtly occur at different time points depending on cell type, mode and concentration of stimuli [ 10 , 11 , 12 , 13 ]. IRAK3 also promotes expression of inflammatory mediators (NFκB and IL-8) upon stimulation with IL-1 or IL-1β [ 5 , 7 ], and induces IL-6, IL-5 and IL-13 production in response to extracellular IL-33 stimulation [ 12 ].…”

Genomic signatures of desert adaptation at gene-rich regions in zebu cattle from the African drylands

“…The gene is likely involved in immune responses against bacterial infection, particularly the causative agent of tuberculosis, Mycobacterium bovis. Specifically, MARCO plays a role in the phagocytosis of bacteria, including Mycobacterium species and Salmonella species, as demonstrated in previous studies involving microbial infections in mice and zebrafish (Dorrington et al, 2013;Benard et al, 2014). Polymorphisms in the gene have also been associated with pulmonary tuberculosis (TB) in humans caused by Mycobacterium tuberculosis (Ma et al, 2011;Bowdish et al, 2013;Thuong et al, 2016).…”

“…We found the interleukin 1 receptor-associated kinase 3 (IRAK3) gene in the proximity of the HMGA2 gene. IRAK3 is a crucial modulator of inflammatory responses and negatively regulates Toll-like receptor signalling pathways involved in innate host defence (Nguyen et al, 2020). It has been reported under positive selection in non-African humped cattle adapted to tropical climatic conditions (Porto-Neto et al, 2014;Naval-Sánchez et al, 2020).…”