Induction of a broad spectrum of inflammation-related genes by Coxsackievirus B3 requires Interleukin-1 signaling.
Coxsackievirus B3 (CVB3) is a major cause of acute and chronic forms of myocarditis. Previously, direct viral injury and post-infectious autoimmune response were suspected as main pathogenetic mechanisms. However, induction of pro-inflammatory cytokines may be crucial for pathogenesis in spite of host protein shut off caused by CVB3 replication. We investigated the global expression profile of pro-inflammatory genes induced by acute and persistent (carrier state) CVB3 infection in human fibroblast cell cultures with DNA microarrays, quantitative RT-PCR and ELISA. Rapid induction of a typical spectrum of about 30 inflammation-related genes (e.g., PTGS2, CCL2, IL-1β, IL-6, IL-8, CSF2, MMP-1, MMP-3, and MMP-15) suggested an essential, autocrine role of IL-1. This hypothesis was confirmed by over-expression of IL-1RI, which resulted in a cytokine response upon CVB3 infection in HEK 293 cells otherwise refractory to CVB3-caused gene expression. Blocking IL-1 receptor type I (IL-1RI)-signaling during CVB3 infection with an IL-1 receptor antagonist (IL-1ra) as well as knockdown of IL-1RI using siRNA abrogated cytokine response in human fibroblasts. Both IL-1α and IL-1β are relevant for the induction of inflammation-related genes during CVB3 infection as shown by neutralization experiments. Paracrine effects of IL-1 on the subset of non-infected cells in carrier state infected fibroblast cultures enhanced induction of inflammation-related genes.


CONCLUSIONS
A broad spectrum of inflammatory cytokines was induced by CVB3 replication via a pathway that requires IL-1 signaling. Our results suggest that IL-1ra may be used as a therapeutic agent to limit inflammation and tissue destruction in myocarditis.
Institute of Virology, Hannover Medical School, Hannover, Germany. fabienne.rehren@gmx.de
Fabienne
F
Rehren
Barbara
B
Ritter
Oliver
O
Dittrich-Breiholz
Andreas
A
Henke
Elena
E
Lam
Semra
S
Kati
Michael
M
Kracht
Albert
A
Heim
D002460:Cell Line; D029822:Enterovirus B, Human / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D020869:Gene Expression Profiling; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000276:immunology*; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
D007375:Interleukin-1