Abstract
Purpose: :
Suppressor of Cytokine Signaling (SOCS) proteins are induced upon cytokine signaling and act as negative feedback regulators by interfering with the JAK/STAT pathway. Whereas SOCS1 inhibits signaling induced by Type 1 and Type 2 interferon (IFN), SOCS3 inhibits signaling by IL-6 family cytokines. Previous work by us determined that SOCS1 and SOCS3 mRNA and protein levels were significantly upregulated in MCMV-infected eyes of mice with MAIDS during progression of retinitis suggesting a pathogenic role for these cytokine regulators during MAIDS-related MCMV retinitis. Studies were therefore performed to characterize SOCS1 and SOCS3 expression during systemic MCMV infection of healthy mice versus MAIDS mice with focus on splenic cells.
Methods: :
Groups of healthy C57BL/6 mice or C57BL/6 mice with MAIDS were injected intraperitonally with MCMV or mock-injected. At 1 - 10 days after injection, splenic cells were collected from all mice and subjected to real time RT-PCR assay for quantification of SOCS1, SOCS3, MCMV IE1, MCMV gH, IFN-β, IFN-γ, and/or IL-6 mRNA levels.
Results: :
When compared with splenic cells from mock-infected healthy mice, splenic cells from MCMV-infected healthy mice showed detectable SOCS1 and SOCS3 mRNA levels that peaked significantly at day 2 postinfection (pi), but declined thereafter, and by days 7 and 10 pi were at levels less than those found in mock-infected mice. Splenic cells collected from MAIDS animals with systemic MCMV infection showed a similar pattern of SOCS1 and SOCS3 mRNA synthesis including a significant decrease in mRNA levels late in the course of infection. Splenic cells collected from healthy mice at 2 days pi also showed a significant increase in levels of IFN-γ and IL-6 mRNAs, but not IFN-β mRNA. MCMV infection of splenic cells as assessed by detection of MCMV-specific IE1 and gH mRNAs was observed at days 1 - 4 pi, but was undetectable at days 7 and 10 pi.
Conclusions: :
SOCS1 and SOCS3 may play a role in the pathogenesis of systemic MCMV infection during health and MAIDS by affecting IFN-γ and IL-6 production, respectively. Our findings serve to set baseline data for future studies on the mechanism(s) by which SOCS1 and SOCS3 impact onset and progression of MAIDS-related MCMV retinitis.
Keywords: cytomegalovirus • retinitis • microbial pathogenesis: experimental studies