We describe here an approach to pharmacologically interrogate the PI3-K family. Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. Might reflect the susceptibility of the patient's innate immune system to tolerization. Is whether individual differences in the severity and clinical course of infection An intriguing question raised by these findings Consequent to impaired negative regulation the hostīecomes “intolerant” of continued exposure to bacteria and thus mounts a perpetual Immune response implicating impaired negative regulation of inflammatory signaling Herein, we provide a mechanistic explanation for this unanticipated host Paradigms, our prior study using a mouse model of Lyme disease demonstrated an associationīetween CD14 deficiency, increased bacterial burden, and more severe and persistentĭisease. Of work underpins two well-established paradigms which cite the primacy of CD14 inįacilitating TLR recognition of microbes to initiate proinflammatory signaling eventsĪnd the importance of p38 in augmenting such responses. Similarly, blocking downstream p38 kinaseĪctivity dampens the cellular response to these same microbial stimuli.
In vitro evidence demonstrates that blocking CD14 recognition of bacterial components ablates Macrophages express CD14 which partners with Toll-like receptor 2/1 to recognize bacterialīorrelia burgdorferi, the causative agent of Lyme disease. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlieĭevelopment of infectious chronic inflammatory syndromes. Importantly, these altered signaling events and the higher cytokine production observedĬan be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing The induction of tolerance in macrophages and engendering more severe and persistentī. Leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising Rafts, hyperphosphorylation of AKT, and reduced activation of p38.
CD14 deficiency results in increased localization of PI3K to lipid In part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative Herein, this paradigm is challenged by demonstratingīorrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbesīy certain TLRs to initiate pro-inflammatory signaling events and the importance of
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