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Interferon‐α suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist
Author(s) -
Tajuddin Tariq,
Ryan Elizabeth J,
Norris Suzanne,
Hegarty John E,
O'Farrelly Cliona
Publication year - 2010
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2010.06281.x
Subject(s) - medicine , neutropenia , agonist , peripheral blood mononuclear cell , granulocyte colony stimulating factor , immunology , granulocyte , tlr7 , cytokine , interferon , receptor , in vitro , chemotherapy , toll like receptor , biology , innate immune system , biochemistry
Background and Aim: Neutropenia, a major side‐effect of interferon‐α (IFN‐α) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G‐CSF), an important growth factor for neutrophils. We hypothesized that IFN‐α might suppress G‐CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll‐like receptor (TLR) agonist might overcome this suppression. Methods: Fifty‐five patients who were receiving IFN‐α/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G‐CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme‐linked immunosorbent assay following 18 h of culture in the absence or presence of IFN‐ α or the TLR7/8 agonist, CL097. Results: Therapeutic IFN‐α caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G‐CSF. The reduction in ANC over the course of IFN‐α treatment was paralleled by a decrease in the ability of PBMCs to produce G‐CSF. In vitro G‐CSF production by PBMCs was suppressed in the presence of IFN‐α; however, co‐incubation with a TLR7/8 agonist significantly enhanced G‐CSF secretion by cells obtained both from HCV patients and healthy controls. Conclusions: Suppressed G‐CSF production in the presence of IFN‐α may contribute to IFN‐α‐induced neutropenia. However, a TLR7/8 agonist elicits G‐CSF secretion even in the presence of IFN‐α, suggesting a possible therapeutic role for TLR agonists in treatment of IFN‐α‐induced neutropenia.