Toll-like receptor 4 signaling promotes invasion of hepatocellular carcinoma cells through MKK4/JNK pathway.

Toll-like receptor (TLR) 4-mediated signaling has been shown to be important to cell survival, invasion and metastasis in a variety of cancers. The present study aimed to explore the role and downstream pathways of TLR4 signaling in the invasion of hepatocellular carcinoma (HCC) cell lines. We found that LPS, the agonist of TLR4, notably enhanced the invasiveness of HCC cells and the expression of MMP2 and MMP9, as well as the production of IL-6 and TNFα. LPS treatment dramatically increased the TLR4 expression on HCC cells surface and MKK4/JNK activation, while knockdown of TLR4 inhibited the LPS-induced invasion and the phosphorylation of MKK4 and JNK. Furthermore, silencing of MKK4 or inhibition of JNK activity led to impaired invasiveness of HCCs, low expression level of MMPs and TLR4, as well as limited production of cytokines. However, LPS stimulation only triggered moderate activation of NF-кB. Silencing of NF-кB or NF-кB inhibitor had no obvious effect on the invasive ability of HCCs and TLR4 expression, but suppressed IL-6 and TNFα production. These findings suggested that LPS-TLR4 signaling enhanced the invasiveness of HCCs mainly through MKK4/JNK pathway.

Complex alternative splicing of the myelin oligodendrocyte glycoprotein gene is unique to human and non-human primates.

Myelin/oligodendrocyte glycoprotein (MOG) is a minor integral membrane protein specific to CNS myelin, encoded by a gene located in the major histocompatibility complex. MOG is an highly encephalitogenic autoantigen and a target for autoaggressive immune responses in CNS inflammatory demyelinating diseases. We performed transcriptomic analyses for a gene expressed only in mammalian CNS, myelin oligodendrocyte glycoprotein (MOG). Complex splicing patterns were exclusively found in primates and not in mice, unlike patterns found for other myelin protein genes. In addition to those shared with rodents, these multiple MOG isoforms likely support functions unique to the primate order, in particular maintenance of myelin structure, intracellular signaling, and modulation of CNS autoimmunity via exposure of specific MOG determinants. Developmentally, in human brain the splice variants of MOG appear at a late stage compared to the major isoform, coincidental with myelination and myelin maturation, unlike other myelin proteins. These findings are discussed within the framework of a biological basis for phenotype diversity in recent mammalian evolution and for the notoriously variable clinical expression of diseases such as multiple sclerosis.

Marmoset fine B cell and T cell epitope specificities mapped onto a homology model of the extracellular domain of human myelin oligodendrocyte glycoprotein.

Aberrant association of autoantibodies with myelin oligodendrocyte glycoprotein (MOG), an integral membrane protein of the central nervous system (CNS) myelin, has been implicated in the pathogenesis of multiple sclerosis (MS). Sensitization of nonhuman primates (Callithrix jacchus marmosets) against the nonglycosylated, recombinant N-terminal domain of rat MOG (residues 1-125) reproduces an MS-like disease in which MOG-specific autoantibodies directly mediate demyelination. To assess the interrelationship between MOG structure and the induction of autoimmune CNS diseases and to enable structure-based rational design of therapeutics, a homology model of human MOG(2-120) was constructed based on consensus residues found in immunoglobulin superfamily variable-type proteins having known structures. Possible sites for posttranslational modifications and dimerization have also been identified and analyzed. The B cell and T cell epitopes have been identified in rat MOG-immunized marmosets, and these sequences are observed to map primarily onto accessible regions in the model, which may explain their ability to generate potent antibody responses.