Induction of p38- and gC1qR-dependent IL-8 expression in pulmonary fibroblasts by soluble hepatitis C core protein.
BACKGROUND
Recent studies suggest that HCV infection is associated with progressive declines in pulmonary function in patients with underlying pulmonary diseases such as asthma and chronic obstructive pulmonary disease. Few molecular studies have addressed the inflammatory aspects of HCV-associated pulmonary disease. Because IL-8 plays a fundamental role in reactive airway diseases, we examined IL-8 signaling in normal human lung fibroblasts (NHLF) in response to the HCV nucleocapsid core protein, a viral antigen shown to modulate intracellular signaling pathways involved in cell proliferation, apoptosis and inflammation.


METHODS
NHLF were treated with HCV core protein and assayed for IL-8 expression, phosphorylation of the p38 MAPK pathway, and for the effect of p38 inhibition.


RESULTS
Our studies demonstrate that soluble HCV core protein induces significant increases in both IL-8 mRNA and protein expression in a dose- and time-dependent manner. Treatment with HCV core led to phosphorylation of p38 MAPK, and expression of IL-8 was dependent upon p38 activation. Using TNFalpha as a co-stimulant, we observed additive increases in IL-8 expression. HCV core-mediated expression of IL-8 was inhibited by blocking gC1qR, a known receptor for soluble HCV core linked to MAPK signaling.


CONCLUSIONS
These studies suggest that HCV core protein can lead to enhanced p38- and gC1qR-dependent IL-8 expression. Such a pro-inflammatory role may contribute to the progressive deterioration in pulmonary function recently recognized in individuals chronically infected with HCV.
Moorman
Jonathan P
JP
Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA. moorman@mail.etsu.edu
Fitzgerald
S Matthew
SM
Prayther
Deborah C
DC
Lee
Steven A
SA
Chi
David S
DS
Krishnaswamy
Guha
G
D002352:Carrier Proteins / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000276:immunology*; D012995:Solubility; D014758:Viral Core Proteins / Q000008:administration & dosage* / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
C087299:C1QBP protein, human; D002352:Carrier Proteins; D016209:Interleukin-8; D024101:Mitochondrial Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D048051:p38 Mitogen-Activated Protein Kinases