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Thrombin stimulates IL-6 and IL-8 expression in cytomegalovirus-infected human retinal pigment epithelial cells
Martin Scholz1, Jens-Uwe Vogel, Gerold Höver
1Institut für Medizinische Virologie, Zentrum der Hygiene, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Abstract:
Recently, we reported that thrombin specifically stimulates protease-activated receptor-1 (PAR-1) signaling in RPE entailing inhibition of Sp1 dependent HCMV replication. We now studied whether thrombin modulates the expression of the proinflammatory cytokine/chemokines IL-6 and IL-8 in mock- and cytomegalovirus-infected human retinal pigment epithelial cells (RPE). Our data show that thrombin/PAR-1 stimulates IL-6 and IL-8 gene transcription and protein secretion in both mock- and HCMV-infected RPE. Thrombin/PAR-1-mediated signaling stimulated PKC and NF-kappaB-dependent IL-6 and IL-8 gene expression via phosphoinositide 3-kinase and further downstream via p42/44 and p38 MAPKs. Thus, thrombin/PAR-1-mediated IL-6/IL-8 gene expression is uncoupled from Sp1 inhibition and may support proinflammatory pathomechanisms probably involved in hemorrhage/HCMV retinitis progression.
Insights
Thrombin, via protease-activated receptor-1 (PAR-1), stimulates the release of inflammatory cytokines IL-6 and IL-8 in retinal cells. This process, independent of Sp1 inhibition, may contribute to inflammatory eye diseases like retinitis.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Thrombin signaling through protease-activated receptor-1 (PAR-1) in retinal pigment epithelial (RPE) cells was previously shown to inhibit human cytomegalovirus (HCMV) replication by affecting Sp1.
- The role of thrombin/PAR-1 in modulating inflammatory responses in RPE cells, particularly in the context of viral infections, remained unclear.
Purpose of the Study:
- To investigate whether thrombin modulates the expression of the proinflammatory cytokines IL-6 and IL-8 in human RPE cells.
- To determine the signaling pathways involved in thrombin/PAR-1-mediated regulation of IL-6 and IL-8 in both mock- and HCMV-infected RPE cells.
Main Methods:
- Human RPE cells were treated with thrombin under mock-infected and HCMV-infected conditions.
- Gene transcription and protein secretion of IL-6 and IL-8 were analyzed.
- Signaling pathways including protein kinase C (PKC), nuclear factor-kappaB (NF-kappaB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs) were investigated.
Main Results:
- Thrombin/PAR-1 significantly stimulated IL-6 and IL-8 gene transcription and protein secretion in both mock- and HCMV-infected RPE cells.
- Thrombin/PAR-1-mediated signaling activated PKC and NF-kappaB pathways, leading to increased IL-6 and IL-8 expression.
- The signaling cascade involved PI3K and downstream p42/44 and p38 MAPKs.
Conclusions:
- Thrombin/PAR-1 signaling promotes the expression of IL-6 and IL-8 in RPE cells, irrespective of HCMV infection status.
- This pro-inflammatory cytokine induction is mediated by PKC, NF-kappaB, PI3K, and MAPK pathways.
- The thrombin/PAR-1-induced IL-6/IL-8 expression is uncoupled from Sp1 inhibition and may contribute to inflammatory pathomechanisms in conditions like hemorrhage/HCMV retinitis.
