The effects of feline retroviruses on cytokine expression.

To identify potential roles of cytokines in retroviral pathogenesis, we used reverse transcription-quantitative competitive polymerase chain reaction (RT-qcPCR) assays to characterize mRNA levels of 19 different lymphokines, chemokines, monokines and hematopoietic growth factors in three feline cell lines productively infected with subgroup A feline leukemia virus (FeLV-A) or various feline immunodeficiency virus (FIV) strains. Infection of a CD8+, CD5- large granular lymphocyte (LGL) cell line with FeLV-A activated expression of interleukin-7 (IL-7), induced modest (4-fold) increases in granulocyte/macrophage colony-stimulating factor (GM-CSF) and leukemia inhibitory factor (LIF) transcripts, and decreased transforming growth factor-beta (TGF-beta) mRNA (4-fold). The LGL cells were not susceptible to infection by FIV. Infection of MYA-1 cells, a CD4+ T-lymphoblastoid cell line, with FeLV-A activated expression of macrophage inflammatory protein-1alpha (MIP-1alpha), increased transcript levels of GM-CSF (8-fold), macrophage CSF (M-CSF) (16-fold) and stem cell factor (SCF) (250-fold), and decreased (4-fold) expression of IL-10 and tumor necrosis factor-alpha (TNF-alpha). Productive infection with four different FIV molecular clones caused progressive MYA-1 cell death; however, the mRNA expression profiles were unchanged except for 2- to 4-fold increases in M-CSF and 16- to 500-fold increases in SCF. Thus, FIV-induced MYA-1 cytopathicity was not associated with dysregulation of pro-apoptotic or survival factor transcript levels. Lastly, productive infection of PNI cells, a marrow-derived fibroendothelial cell line, with FeLV-A or any of three FIV strains induced 4-fold higher levels of IL-12p40 transcripts and variably higher levels (4- to 64-fold) of GM-CSF. Two viral strains, the FIV-14 molecular clone and the clinical isolate FIV-5122, caused syncytia formation and unique activation of IL-1beta and stromal cell-derived factor-1 (SDF-1) expression, suggesting a potential role for those factors in viral spread and/or cytopathicity. In addition, infection with FIV-5122, but not the other FIV strains or FeLV-A, induced significant increases in mRNA levels of the hematopoietic inhibitors TNF-alpha and MIP-1alpha, along with increased concentrations of soluble proteins in culture supernatants. Consistent with this, supernatant from FIV-5122 infected PNI cells suppressed hematopoietic progenitor growth in colony assays, compared to supportive activities in supernatants from other infected or uninfected PNI cell cultures. Together, these data demonstrate that feline retroviruses alter cytokine mRNA levels in general and strain-specific patterns. These changes may result in specific alterations in cell function and contribute to retroviral pathogenesis. Our observations provide a basis for directed studies of candidate factors within the hematopoietic, thymic and lymphoid microenvironments.