The TLRs play a key role in host defense against infection and injury, and mounting evidence suggests that these receptors may also play a role in diseases such autoimmunity, atherosclerosis, and cancer. Activation of TLRs on macrophages results in the production of multiple soluble mediators including the key inflammatory cytokines, TNF and IL-6. Thus, the intracellular signaling mechanism by which TLRs signal is a subject of great interest. As well as activating the NF-κB and MAPK pathways, TLR engagement leads to tyrosine kinase activation within minutes. Src family kinases (SFKs) are the largest nonreceptor tyrosine kinase family with nine members: Src, Hck, Lyn, Fyn, Fgr, Blk, Lck, Yes, and Ylk. The role of the SFKs in TLR signaling has been an area of much controversy, with conflicting findings between studies using chemical inhibitors and knockout mice. Using primary human macrophages in combination with adenoviral overexpression and small interfering RNA knockdown studies, we show that the SFK, Hck, has a pre-eminent role in LPS/TLR4-induced TNF and IL-6 production. Hck kinase mediates TLR4-induced transcription of both TNF and IL-6 by a mechanism that involves neither the NF-κB nor the MAPK pathways, but rather leads to AP-1 binding with a complex of c-fos and JunD. These data highlight the importance of Hck as an active component in LPS-induced TLR signaling and suggest the possibility of targeting this kinase for the alleviation of excessive inflammation.
The activity of tyrosine kinases is central to many cellular processes, and accumulating evidence suggests that their role in inflammation is no less profound. Three main tyrosine kinase families, the Src, Tec and Syk kinase families are intimately involved in TLR signalling, the critical first step in cellular recognition of invading pathogens and tissue damage. Their activity results in changes in gene expression in affected cells. Key amongst these genes are the cytokines, which orchestrate both the duration and extent of inflammation. Tyrosine kinases also play important roles in cytokine function, and are implicated in signalling through both pro- and anti-inflammatory cytokines such as TNF, IL-6 and IL-10. Thus, strategies to modulate tyrosine kinase activity have significant therapeutic potential in combating the chronic inflammatory state that is typical of many major health issues that face us today, including Rheumatoid Arthritis, Cardiovascular disease and cancer. Here we review current knowledge of the role of tyrosine kinases in inflammation with particular emphasis on their role in TLR signalling.
Obesity is regarded as a pro‐inflammatory state. It is associated with low circulating levels of the adipokine, adiponectin, which is considered to be an anti‐inflammatory. However, adiponectin knockout mice do not consistently demonstrate pro‐inflammatory phenotypes, suggesting more complexity in the in vivo immunomodulatory effects of adiponectin than originally anticipated. Moreover, adiponectin exerts pro‐inflammatory effects in some experimental systems. This contradiction has been resolved by hypothesizing that adiponectin induces tolerance to inflammatory stimuli, notably Toll‐like receptor (TLR) ligands. We noticed that this effect resembled lipopolysaccharide (LPS) tolerance and therefore tested adiponectin from a variety of sources for LPS contamination. All adiponectin tested carried low levels of LPS in the range of 1–30 pg/μg of adiponectin, sufficient to produce final LPS concentrations in the pg/ml range under experimental conditions. We found that induction of tolerance to TLR ligands by adiponectin in human monocyte‐derived macrophages could be reproduced by such LPS concentrations. Moreover, the LPS antagonist, polymixin B, substantially inhibited induction of tolerance by adiponectin. Furthermore, polymixin B and a naturally occurring antagonist LPS were able to partially attenuate induction of tumour necrosis factor‐α and interleukin‐6 in human monocyte‐derived macrophages by adiponectin. Polymixin B also inhibited nuclear factor‐κB and mitogen‐activated protein kinase signalling elicited by adiponectin. We therefore propose that some of adiponectin’s immunomodulatory effects, in particular, its TLR‐tolerising actions in human monocyte‐derived macrophages, may be confounded by induction of tolerance by contaminating LPS.
Subject of this study is the predictive value of baseline heart rate (HR) response to simulated diving. Twentyseven male volunteers aged 20-25 performed apneic face immersion in cold water, while ECG was recorded. Both the initial HR increase and the following bradycardic response significantly correlated to resting HR. To optimally estimate the reference HR (mean HR or the longest 512-RR-intervallong time series or minimum of moving HR average at given lengths), we compared three different approaches, based on the best correlations between the evoked responses, HRV measures and resting baseline. Our data indicate lack of universal HR reference useful to predict resulting diving response. The longest RRi observed across preceding time window is apparently the best indicator of the diving bradycardic response, while the initial HR increase and time of voluntary apnea corresponds to the longtime HR average. Index Terms-diving reflex, baseline heart rate, HRV
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