IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression

Abstract

Human cytomegalovirus virus (CMV) is a major cause of morbidity and mortality in immunocompromised individuals. Recently, a novel group of cytokines [interleukin (IL)-28A/B and IL-29, also termed interferon (IFN)-lambdas] has been described. Here, we demonstrate that intestinal epithelial cell (IEC) lines as well as murine and human colonic tissue express the IFN-lambda receptor subunits IL-28R and IL-10R2. IL-28A and IL-29 binding to their receptor complex activates ERK-1/2 and stress-activated protein kinase/c-Jun NH2-terminal kinase MAPKs and Akt, resulting in increased IL-8 protein expression. IFN-lambdas also induce phosphorylation of signal transducer and activator of transcription 1 and significantly increase mRNA expression of suppressor of cytokine signaling 3 and the antiviral proteins myxovirus resistance A and 2',5'-oligoadenylate synthetase. These signals result in an up to 83% reduction of cells positive for human CMV immediate-early protein after human CMV infection. In mice, IL-28A mRNA expression is upregulated after infection with murine CMV in vivo. Both IL-28A and IL-29 significantly decrease cell proliferation but have no effect on Fas-induced apoptosis. In conclusion, IECs express functional receptors for IFN-lambdas, which mediate antiviral and antiproliferative signals in IECs, suggesting a potential for therapeutic use in certain viral infections and as (antiproliferative) anticancer therapy.

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…IL-29 is a recently discovered cytokine that has similar mode of anti-viral activity as IFN-I (Dumoutier et al 2004;Meager et al 2005;Ank et al 2008;Uze and Monneron 2007). However, IFN-III seems to have a more specialized role in epithelial and mucosal antiviral defense (Brand et al 2005;Okabayashi et al 2011) since the expression of IFN-III receptor is restricted to renal and mucosal epithelial surfaces (Iversen et al 2010;Li et al 2009;Sommereyns et al 2008;Mordstein et al 2010). Except for one recent study from our laboratory reporting decreased IL-29 secretion by pDCs from aged, there is a scarcity of information regarding the status of IL-29 production during aging.…”

Structure and function of interleukin-22 and other members of the interleukin-10 family

“…The antiviral protection conferred by IFN-ks has been confirmed in various cell lines, including HeLa, HuH7 hepatoma, and HT-29 colon epithelial cells and with different viruses, including Sindbis virus, dengue virus, vesicular stomatitis virus, and human cytomegalovirus [97,107]. Mouse deficient in the gene encoding IFN-kR1, recently allowed to demonstrate the respective roles of type I and type II IFN in an influenza infection model.…”

Genome-wide prediction of interferon family members of tree shrew and their molecular characteristics analysis

“…在研究病毒干扰现象时发现的一 类性质待定的"可溶性物质" 。直至 1980 年, Taniguchi et al(1980a;1980b)首次克隆了人 IFN-α 和 IFN-β 全长 cDNA, 由此，IFN 成为研究最早的一类 细胞因子。现已证明, IFN 为多成员家族, 它们普遍 存在于脊椎动物中, 是多种类细胞在受到"危险信 号"刺激后分泌的糖蛋白。IFN 作为机体抵抗病毒 感染的第一道防线, 具有抗病毒、抗肿瘤、抑制细 胞增殖及免疫调节等多重作用 (Ank et al, 2006;Brand et al, 2005;Kotenko et al, 2003;Österlund et al, 2005)。依据基因序列、染色体定位和受体特异性等 特点, 可将 IFN 分为 3 种类型 (Kotenko et al, 2003;Samarajiwa et al, 2009)。I 型 IFN 包括 9 个亚型, 即 α、β、ε、κ、τ、ω、ζ、ν、δ; II 型 IFN 仅有 IFN-γ 1 种; III 型 IFN 由 IFN-λ1(IL-29)、 IFN-λ2(IL-28A) 和 IFN-λ3(IL-28B)构成。 树鼩(tree shrew, Tupaia belangeri), 其外形酷 似松鼠 (Cao et al, 2003), 在进化关系上与灵长类动 物较为接近 (Novacek, 1992;Waddell et al, 2001)。 Walter et al(1996)证实了我国学者早在 80 年代的发 现 (Su et al, 1987) (Schwartz et al, 2000(Schwartz et al, , 2003 进行序列比对。采用 GENSCAN (Burge & Karlin, 1998 图 3 树鼩、人 IFN-γ 序列比对 Fig.3 Amino acid sequence alignment of tree shrew and human IFN-γ 注释同图 1(Notes are the same as those in Fig. 1 …”