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Journal of immunology (Baltimore, Md. : 1950) (1)
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TIPE2 Controls Innate Immunity to RNA by Targeting the PI3K–Rac Pathway
Chen, Youhai H.
Journal of immunology (Baltimore, Md. : 1950)
RNA receptors such as TLR3 and RIG-I/MDA5 play essential roles in innate immunity to RNA viruses. However, how innate immunity to RNAs is controlled at the molecular level is not well understood. We describe here a new regulatory pathway of anti-RNA immunity that comprises PI3K (phosphoinositide kinase-3), its target GTPase Rac, and the newly described immune regulator TIPE2 (TNF-α-induced protein 8 like-2, or TNFAIP8L2). Poly (I:C), a double-stranded RNA receptor ligand, activates Rac via its guanine nucleotide exchange factor Tiam; this leads to the activation of cytokine genes, and paradoxically down-regulation of Tipe2 gene. TIPE2 is a negative regulator of immunity; its deficiency leads to hyper-activation of the PI3K–Rac pathway as exemplified by enhanced AKT, Rac, PAK, and IRF3 activities. As a consequence, TIPE2 knockout myeloid cells are hyper-reactive to Poly (I:C) stimulation, and TIPE2 knockout mice are hypersensitive to Poly (I:C)-induced lethality. These results indicate that TIPE2 controls innate immunity to RNA by targeting the PI3K–Rac pathway. Therefore, manipulating TIPE2 or Rac functions can be effective for controlling RNA viral infections.
TNFAIP8; RNA; Innate Immunity; Rac; TLR; PI3K
Significance of decoy receptor 3 (Dcr3) and external-signal regulated kinase 1/2 (Erk1/2) in gastric cancer
Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, is associated with anti-tumor immunity suppression. It is highly expressed in many tumors, and its expression can be regulated by the MAPK/MEK/ERK signaling pathway. The MAPK/MEK/ERK pathway has been reported to be a regulator in tumor occurrence, development and clonal expansion. External-signal regulated kinase (ERK) is a vital member of this pathway.
The expression of DcR3 and ERK1/2 in tumor tissues of gastric cancer patients was significantly higher than the non-cancerous group (P < 0.05). There was no statistical difference among tumor tissues from patients with different ages or gender, and even of different differentiation (P > 0.05). However, in patients with stage I gastric cancer, the DcR3 and ERK1/2 levels were significantly lower than patients with more advanced stages.
DcR3 and ERK1/2 play a vital role in the development of gastric cancer, and they may be new markers for indicating the efficiency of gastric cancer treatment in the future.
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