Infection of murine keratinocytes with herpes simplex virus type 1 induces the expression of interleukin‐10, but not interleukin‐1α or tumour necrosis factor‐α

Abstract

SUMMARYHerpes simplex virus (HSV) is known to possess several mechanisms whereby it can evade the normal host immune defences. In this study the expression of the immunosuppressive cytokine, interleukin (IL)-10, was monitored following infection of a murine keratinocyte cell line (PAM-212) and compared with the expression of two proin¯ammatory cytokines: IL-1a and tumour necrosis factor (TNF)-a. The PAM-212 cells were infected at a multiplicity of 0 . 5 with a clinical isolate of HSV type 1, and the mRNA of the three cytokines was assessed by semiquantitative reverse transcription±polymerase chain reaction (RT±PCR) over the following 24 hr. By 12 hr postinfection the amount of IL-10 mRNA had increased signi®cantly to ®ve-fold greater than that found in uninfected cells (P<0 . 01), and this elevated level was maintained until at least 24 hr postinfection. In contrast, IL-1a and TNF-a mRNAs were not signi®cantly up-regulated by the HSV infection. Immunostaining with an IL-10 monoclonal antibody (mAb) revealed that cytoplasmic IL-10 protein had increased by 6 ±12 hr postinfection. This quantity was further increased at 24 hr postinfection, when the viral cytopathic effect was apparent. Viral replication was necessary, but not suf®cient on its own, for IL-10 induction. Experiments with HSV mutants lacking functional transactivating factors suggested that the viral transactivating proteins ICP-0 and VP-16 may be necessary for HSV-induced IL-10 expression. Thus, the up-regulation in the expression of IL-10 mRNA and protein induced by HSV early in the infection of keratinocytes represents a speci®c response and may be part of the viral strategy to avoid local immune defence mechanisms in the skin.

Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10

“…One study demonstrated that immortalized mouse keratinocytes infected with HSV had increased levels of IL-10 mRNA (72). However, these investigators did not analyze IL-10 protein levels, and mRNA and protein levels do not always correlate with one another.…”

Differential Responses of Murine Vaginal and Uterine Epithelial Cells Prior to and Following Herpes Simplex Virus Type 2 (HSV‐2) Infection

“…It has also been documented that HSV‐1 specifically inhibits gene transcription of IL‐1 α in keratinocytes in vitro 33 . Murine keratinocyte cell lines respond to HSV‐1 with production of IL‐10 15 which is a classic immunoregulatory cytokine. On the basis of our results, it would therefore appear that HSV‐2 is specifically interfering with the production of cytokines from uterine EC cultures.…”

“…Models of HSV‐1 infection show that the virus can suppress pro‐inflammatory cytokine secretion 31 . IL‐1 α is not secreted from corneal ECs or keratinocytes following infection in vitro 15,32 . It has also been documented that HSV‐1 specifically inhibits gene transcription of IL‐1 α in keratinocytes in vitro 33 .…”

“…There is some information on cytokine secretion from other types of EC in response to HSV‐1 infection, which is responsible for the majority of skin keratinocyte and corneal epithelial herpes infections. Cultured human corneal keratinocytes produce IL‐8 in response to HSV‐1 infection, 14 and murine keratinocyte cell lines respond to HSV‐1 with production of IL‐10 15 . On the basis of this, we speculated that genital ECs should respond to HSV‐2 infection by initiation/alteration of cytokine secretion.…”

Concurrence of erythema migrans and herpes simplex: first description of a highly unusual dual skin infection

“…It is known that HSV‐1/2 is able to evade the normal host immune reaction via several mechanisms. Zak‐Prelich et al 6 . have demonstrated that up‐regulation of IL‐10 induced by HSV‐1/2 early in the infection of keratinocytes represents a specific response and could be part of a viral immune escape strategy.…”