Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-κB and IRF-3

Abstract

Macrophages and dendritic cells (DCs) play essential roles in host defence against microbial infections. In the present study, it is shown that human monocyte-derived macrophages and DCs express both type I and type III interferons (IFNs) [IFN-a, IFN-b and interleukin 28 (IL-28), IL-29, respectively], tumour necrosis factor alpha and the chemokines CCL5 and CXCL10 after herpes simplex virus 1 (HSV-1) infection. The cytokine-inducing activity of HSV-1 was dependent on viability of the virus, because UV-inactivated virus did not induce a cytokine response. Pretreatment of the cells with IFN-a or IL-29 strongly enhanced the HSV-1-induced cytokine response. Both IFN-a and IL-29 decreased viral immediate-early (IE) gene infected-cell protein 27 (ICP27) transcription, suggesting that IL-29 possesses antiviral activity against HSV-1 comparable to that of IFN-a. Macrophage infection with HSV-1 lacking functional ICP27 (d27-1 virus) resulted in strongly enhanced cytokine mRNA expression and protein production. In contrast, viruses lacking functional IE genes ICP0 and ICP4 induced cytokine responses comparable to those of the wild-type viruses. The activation of transcription factors IRF-3 and NF-kB was strongly augmented when macrophages were infected with the ICP27 mutant virus. Altogether, the results demonstrate that HSV-1 both induces and inhibits the antiviral response in human cells and that the type III IFN IL-29, together with IFN-a, amplifies the antiviral response against the virus. It is further identified that viral IE-gene expression interferes with the antiviral response in human macrophages and ICP27 is identified as an important viral protein counteracting the early innate immune response.

Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues

“…There are three genes for IFN-λ and have been named IFN-λ1, IFN-λ2 and IFN-λ3 (also known as IL-29, IL-28A and IL-28B, respectively). These type I interferons have been shown to be induced by viral infection in the majority of nucleated cells and play a critical role in the innate and adaptive immune responses to viral infection [29]. While the relevance of increased IL-28A expression in AD lesions in the current work remains unclear, the significant levels of this cytokine in AD tissues may suggest the presence of a virus or virus-like infection.…”

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

“…2 These observations, in conjunction with the induction of the IFN-l1/2/3 ligands by a range of viral infections and their ability to rescue virally infected cells, 2,3 have prompted a series of studies that have further investigated the antiviral properties of these cytokines. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] However, the IFN-l ligands also induce the phosphorylation of STAT1, STAT3, STAT5 2,22 and STAT4. 23 Phosphorylation of STAT1, STAT3, STAT5 in particular, suggests more complex properties for the IFN-l ligand family; STAT3 is the signaling mechanism used by members of the IL-10 family (IL-10, IL-19, IL-20, etc.…”

Induction of interleukin-6 in human retinal epithelial cells by an attenuated Herpes simplex virus vector requires viral replication and NFκB activation

“…These results indicate that mechanism of activation of NF-κB depends on the cell type. The observation that acyclovir blocked IL-6 induction in ARPE-19 cells suggests that expression of the HSV α and β genes may be necessary, but is not sufficient for IL-6 induction and that some other event is required (Melchjorsen et al 2006). …”

“…The IL-6 promoter contains binding sites for nuclear factor κB (NF-κB) and the requirement of NF-κB activation for IL-6 induction has been well documented (Rong et al 1992;Matsusaka et al 1993;Patel et al 1998;Amici et al 2001;Paludan 2001;Hargett et al 2006;Melchjorsen et al 2006). We therefore asked if NF-κB was activated in hrR3 infected ARPE-19 cells by measuring translocation of NF-κB from the cytoplasm to the nucleus.…”

“…The IL-6 promoter contains consensus binding sites for the NF-κB family of transcription factors and NF-κB is required for the induction of IL-6 as well as other genes in several cell types (www.nf-kb.org; (Rong et al 1992;Matsusaka et al 1993;Patel et al 1998;Amici et al 2001;Paludan 2001;Hargett et al 2006;Melchjorsen et al 2006). There are seven different NF-κB family proteins that dimerize to form 15 possible complexes: p105, p50, p100, p52, p65, c-rel, and RelB.…”