Squillace, Karen A.

Background In addition to its fundamental functions in mediating the survival, proliferation, and migration of keratinocytes, increasing evidence suggests that the amphiregulin-epidermal growth factor receptor pathway has a major impact on cutaneous inflammation. Transgenic expression of amphiregulin in the epidermis of mice induces skin pathology with striking phenotypic similarity to that of psoriasis. Prominent T-cell and dendritic cell infiltrates are observed in the lesional skin from these mice. Objective In this study, we aimed to identify more fully the effect of amphiregulin on keratinocytes and T cells during cutaneous inflammation through examining relevant cytokines in the lesional skin as well as in human keratinocyte culture. Methods Using a multicytokine enzyme-linked immunosorbent assay, we found that amphiregulin directly induces the production of monocyte chemoattractant protein-1, interleukin-α, and interleukin-8 from keratinocytes in vitro. In addition, we examined the cutaneous expression of T-cell cytokines in amphiregulin transgenic mice compared with wild-type mice using quantitative polymerase chain reaction, which demonstrated upregulation of interferon-γ, vascular endothelial growth factor, and interleukin-4 in amphiregulin transgenic mice. Results and Conclusion Our study suggested that amphiregulin in the epidermis not only induces keratinocyte proliferation but also induces T-cell activation through a complex circuit of proinflammatory cytokines. Elucidating the role of amphiregulin on the generation, interactions, and balance among T-cell subsets will advance the understanding of psoriasis pathogenesis.

ABSTRACTA novel gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), has been identified in patients with prostate cancer and in patients with chronic fatigue syndromes. StandardMus musculuslaboratory mice lack a functional XPR1 receptor for XMRV and are therefore not a suitable model for the virus. In contrast, Gairdner's shrew-mice (Mus pahari) do express functional XPR1. To determine whetherMus paharicould serve as a model for XMRV, primaryMus paharifibroblasts and mice were infected with cell-free XMRV. Infection of cellsin vitroresulted in XMRV Gag expression and the production of XMRV virions. After intraperitoneal injection of XMRV intoMus paharimice, XMRV proviral DNA could be detected in spleen, blood, and brain. Intravenous administration of a green fluorescent protein (GFP) vector pseudotyped with XMRV produced GFP+CD4+T cells and CD19+B cells. Mice mounted adaptive immune responses against XMRV, as evidenced by the production of neutralizing and Env- and Gag-specific antibodies. Prominent G-to-A hypermutations were also found in viral genomes isolated from the spleen, suggesting intracellular restriction of XMRV infection by APOBEC3in vivo. These data demonstrate infection ofMus pahariby XMRV, potential cell tropism of the virus, and immunological and intracellular restriction of virus infectionin vivo. These data support the use ofMus paharias a model for XMRV pathogenesis and as a platform for vaccine and drug development against this potential human pathogen.