Abstract
Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-κB by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3), CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1) exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced ‘germ free’ status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named ‘pseudo-infective endocarditis’ were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction.
Highlights
The transcription factor NF-kB is essential for the regulation of the innate and adaptive immune responses
We have previously observed that the mRNA expression level for several inflammatory cytokines, including IL-1b and TNFa, increases in the cardiac and skin tissues of TAX1BP1-KO mice; more importantly, these mice showed mitral valvulitis and premature death compared to their wild-type (WT) littermates
Total RNA was extracted from three independent tissue samples obtained from the mitral valves of 8- or 16- week-old (-wk) male (WT and TAX1BP1-KO) mice by using laser capture microdissection (LCM), which was followed by total RNA extraction
Summary
The transcription factor NF-kB is essential for the regulation of the innate and adaptive immune responses. NF-kB is activated in response to a wide variety of stimuli, such as inflammation, DNA damage, or nociception [1,2], and is involved in embryogenesis and multiple tissue development [3]. The NF-kB family comprises five proteins including RelA (p65), RelB, c-Rel, NF-kB1, and NFkB2, and their transcriptional activities are tightly controlled to ensure their transient signaling in response to specific stimuli. The NF-kB signaling cascade is usually triggered by sensor molecules, such as toll-like receptor (TLR) family proteins. These proteins can identify the presence of a wide range of microorganisms and transmit that information through phosphorylation relays to downstream kinases, which eventually culminate at the I-kB kinase (IKK). Aberrant activation of NF-kB has been linked to several pathological features such as allergic responses, autoimmune diseases, septic shock, and carcinogenesis in a variety of organs [4]
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