Overexpression of interleukin-4 delays virus clearance in mice infected with respiratory syncytial virus

Abstract

Although interleukin-4 (IL-4) expression has been implicated in vaccine-enhanced respiratory syncytial virus (RSV) disease, its role in mediating the immune response to primary RSV infection remains unclear. To assess the effect of IL-4 production on typical RSV infection, transgenic mice which either overexpress or fail to express IL-4 were challenged intranasally with RSV and their responses were compared to those of the parent strains. IL-4-deficient mice eliminated virus from the lung as quickly as did C57BL/6 controls. In contrast, mice which constitutively overexpress IL-4 showed delayed virus clearance compared with mice of the FVB/N control strain, although peak viral titers did not differ. IL-4 overexpression increased the magnitude of the subsequent antibody response. Lung lymphocytes harvested from IL-4-overexpressing mice post-RSV challenge showed diminished RSV-specific cytolytic activity compared with controls. Both IL-4-deficient and IL-4-overexpressing strains resisted rechallenge. These data imply that constitutive IL-4 expression delays or suppresses the development of a virus-specific cytotoxic lymphocyte population important in clearing primary RSV infection.

IL-13 is associated with reduced illness and replication in primary respiratory syncytial virus infection in the mouse

“…IL-4 has also been shown to influence the CTL response to RSV. Overexpression of IL-4 during RSV infection results in delayed virus clearance and enhanced illness, and is associated with abrogated CD8þ cytolytic T cell activity [10]. The effect on CD8 þ T cell function in this setting is related to altered cytolytic function, and does not alter frequency or IFN-g production in CD8 þ T cells [33,34].…”

“…IL-13 has many of the same immunomodulatory properties as IL-4, partly because both cytokines signal through the IL-4 receptor a-chain [5]. Previously, our group found that IL-4 significantly delayed RSV clearance which was associated with suppression of the development of virus-specific cytotoxic lymphocytes [10], suggesting that IL-13 might have a similar effect. However, IL-13 plays a more critical role in immunity to the gastrointestinal nematode Nippostrongylus brasiliensis and the intracellular parasite Leishmania major than IL-4 [11,12], highlighting divergent phenotypic effects of these cytokines in in vivo models of infection.…”

Improved Protection from Primary Ocular HSV-1 Infection and Establishment of Latency Using Multigenic DNA Vaccines

“…For example, we have previously shown that IL-2 suppresses, but IL-4 enhances, HSV-1 replication in the eye. 27,62,63 Detrimental effects on host animals were also observed in experiments in which IL-4 -expressing transgenic mice were infected with respiratory syncytial virus 64 and in which animals infected with influenza virus infection were treated with recombinant IL-4. 65 In addition, IL-4 expression by a recombinant vaccinia virus has been found to exacerbate infection.…”

NFκB sensing IL‐4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles

“…35,36 The development of controlled-release mechanisms is crucial for translational applications and may avoid potential adverse effects of IL4. [37][38][39] The NFκB-IL4 MSC-based cell therapy significantly improved immunomodulation and minimized adverse effects. The crosstalk between MSCs and M2 macrophages could potentially further enhance bone regeneration.…”