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Myeloid differentiation factor 88 (MyD88) acts as a crucial adaptor molecule for Toll-like receptors (TLRs) and interleukin (IL)-1 receptor signaling. In contrast to the well-studied positive regulation of MyD88 signaling, how MyD88 signaling is negatively regulated still remains largely unknown. Here, we demonstrate for the first time to our knowledge that MyD88 protein undergoes lysine 63 (K63)-linked polyubiquitination, which is functionally critical for mediating TLR-MyD88-dependent signaling. Deubiquitinase CYLD negatively regulates MyD88-mediated signaling by directly interacting with MyD88 and deubiquitinating nontypeable Haemophilus influenzae (NTHi)-induced K63-linked polyubiquitination of MyD88 at lysine 231. Importantly, we further confirmed this finding in the lungs of mice in vivo by using MyD88-/-CYLD-/- mice. Understanding how CYLD deubiquitinates K63-linked polyubiquitination of MyD88 may not only bring insights into the negative regulation of TLR-MyD88-dependent signaling, but may also lead to the development of a previously unidentified therapeutic strategy for uncontrolled inflammation. [ABSTRACT FROM AUTHOR]

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-α-induced NF-κB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-α- or LPS-induced up-regulation of proinflammatory mediators, including TNF-α, lL-1β, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-α- or LPSinduced lung inflammation. Interestingly, vinpocetine inhibits NF-κB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca2+ regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases. [ABSTRACT FROM AUTHOR]