一個終端尿苷醯轉移酶調控TLR4誘導Interleukin-10的機轉

Abstract

Upon pathogen infection, inflammatory cytokines are induced to mount an inflammatory response to defend against pathogens. However, while impaired innate immunity renders the host more vulnerable to pathogenic infection, exceed and prolonged inflammation can cause many diseases. Thereby, anti-inflammatory cytokines, such as IL-10, are expressed at later stage of inflammation to counteract the effects of pro-inflammatory cytokines. To reach a disease-free state, the balance between inflammatory and anti-inflammatory responses must be spatially and temporally controlled. Previously our lab identified Zcchc6 (TUT7), a terminal uridylyltransferase, which was upregulated in murine macrophages upon Lipopolysaccharides (LPS) stimulation. Deprivation of Zcchc6 in macrophages resulted in downregulations of pro-inflammatory cytokines such as IL-6, IL12b and IFNβ, and an upregulation of anti-inflammatory cytokine IL-10. In the study we focus on how Zcchc6 regulates IL-10 expression upon LPS challenge. We found that Zcchc6 does not modulate IL-10 mRNA stability. Rather, Zcchc6 regulates IL-10 transcription. In addition, we demonstrated that STAT1, which is also induced by LPS, binds to the IL-10 promoter upon TLR4 engagement. STAT1 mRNA stability is increased in Zcchc6-deficient macrophages. Our results strongly suggest that Zcchc6 modulates STAT1 mRNA stability, which leads to regulation of IL-10 transcription in response to LPS.