Ringwood L, Li L. The involvement of the interleukin-1 receptor-associated kinases (IRAKs) in cellular signaling networks controlling inflammation. Cytokine 42: 1-7

The Laboratory of Innate Immunity and Inflammation, Department of Biological Sciences, West Campus Drive, Fralin Biotechnology Center, Virginia Tech, Blacksburg, VA 24061, USA.
Cytokine (Impact Factor: 2.66). 05/2008; 42(1):1-7. DOI: 10.1016/j.cyto.2007.12.012
Source: PubMed


Innate immunity and inflammation plays a key role in host defense and wound healing. However, Excessive or altered inflammatory processes can contribute to severe and diverse human diseases including cardiovascular disease, diabetes and cancer. The interleukin-1 receptor-associated kinases (IRAKs) are critically involved in the regulation of intracellular signaling networks controlling inflammation. Collective studies indicate that IRAKs are present in many cell types, and can mediate signals from various cell receptors including toll-like-receptors (TLRs). Consequently, diverse downstream signaling processes can be elicited following the activation of various IRAKs. Given the critical and complex roles IRAK proteins play, it is not surprising that genetic variations in human IRAK genes have been found to be linked with various human inflammatory diseases. This review intends to summarize the recent advances regarding the regulations of various IRAK proteins and their cellular functions in mediating inflammatory signaling processes.

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    • "Several cell types are capable of producing IL-1b, and both neurons and glia express IL-1 receptors (Yabuuchi et al, 1994; Zhang et al, 2010). In astrocytes, IL-1b initiates the formation of IL-1b-signaling intermediates, such as IL-1 receptor-associated kinase (Ringwood and Li, 2008; Flannery and Bowie, 2010) and the subsequent activation of p38, extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB; (Guasch et al, 2007; Huang et al, 2011)). "
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    ABSTRACT: Post-Traumatic Stress Disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we employed stress-enhanced fear learning, an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus. There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, i.c.v., 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the dorsal hippocampus induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL, and suggest that IL-1 signaling in the brain may play a critical role in the development of PTSD.Neuropsychopharmacology accepted article preview online, 28 November 2014. doi:10.1038/npp.2014.317.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.317 · 7.05 Impact Factor
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    • "TLR/IL-1R receptors associate with MyD88 through homotypic interactions between their respective TIR domain. This interaction then allows MyD88 to recruit members of the interleukin-1 receptor-associated kinase (IRAK) family (IRAK1, IRAK2, and IRAK4) through homotypic interactions between their respective Death Domains (DDs) [38] "
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    ABSTRACT: The members of Toll-like receptor/interleukin (IL)-1 receptor (TLR/IL-1R) superfamily play a fundamental role in the immune response. These receptors detect microbial components and trigger complex signalling pathways that result in increased expression of multiple inflammatory genes. On the other hand, an aberrant activation of TLR/IL-1R signalling can promote the onset of inflammatory and autoimmune diseases, raising the interest in the development of therapeutic strategies for the control of their function. In this review, we illustrate the structural and functional features of TLR/IL-1R proteins and discuss some recent advances in the approaches undertaken to develop anti-inflammatory therapeutic drugs. In particular, we will focus on inhibitors, such as decoy peptides and synthetic mimetics, that interfere with protein-protein interactions between signalling molecules of the TLR/IL-1R superfamily. Given their central role in innate and adaptive immune responses, it is foreseen that pharmaceutical modulation of TLR/IL-1R signalling pathways by these drugs might yield clinical benefits in the treatment of inflammatory and autoimmune diseases.
    Mediators of Inflammation 04/2010; 2010:674363. DOI:10.1155/2010/674363 · 3.24 Impact Factor
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    • "However, Smith et al [43] reported that the blockade of TLR4 receptor reduced pulmonary inflammation induced by MV and LPS. On the other hand, Ringwood et al [36] have found that IRAK-3-/- macrophages exhibit enhanced NF-κB activity and elevated expression of various inflammatory cytokines upon stimulation with several TLR ligands. Third, there is a possibility that the repression of IRAK-3 expression could be unrelated to the activation of TLR4 signaling and could be governed by other molecules capable of regulation of inflammation [44]. "
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    ABSTRACT: Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury. Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (VT) (20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IkappaBalpha), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL6) gene expression in the lungs and TNF-alpha and IL-6 protein serum concentrations were analyzed. High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of IkappaBalpha, and a higher lung expression and serum concentrations of pro-inflammatory cytokines. The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections.
    Respiratory research 03/2010; 11(1):27. DOI:10.1186/1465-9921-11-27 · 3.09 Impact Factor
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