title: Ibrutinib enhances IL-17 response by modulating the function of bone marrow derived dendritic cells.
abstract: Ibrutinib (PCI-32765) is an irreversible dual Btk/Itk inhibitor shown to be effective in treating several B cell malignancies. However, limited studies have been conducted to study the effect of this drug on myeloid cell function. Hence, we studied the effect of ibrutinib treatment on TLR-4 mediated activation of bone marrow derived dendritic cell culture (DCs). Upon ibrutinib treatment, LPS-treated DCs displayed lower synthesis of TNF-α and nitric oxide (NO) and higher induction of IL-6, TGF-β, IL-10 and IL-18. While ibrutinib dampened MHC-II and CD86 expression on DCs, CD80 expression was upregulated. Further, ibrutinib-treated DCs promoted T cell proliferation and enhanced IL-17 production upon co-culture with nylon wool enriched T cells. Taken together, our results indicate that ibrutinib modulates TLR-4 mediated DC activation to promote an IL-17 response. We describe a novel mode of action for ibrutinib on DCs which should be explored to treat other forms of cancer besides B cell malignancies.
authors.affiliation: Department of Microbiology; The Ohio State University ; Columbus, OH USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Natarajan
authors.affiliation: Department of Pathology; The Ohio State University Medical Center ; Columbus, OH USA.
authors.forename: Cesar
authors.initials: C
authors.lastname: Terrazas
authors.affiliation: Department of Environmental Health Sciences; The Ohio State University College of Public Health ; Columbus, OH USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Oghumu
authors.affiliation: Department of Pathology; The Ohio State University Medical Center ; Columbus, OH USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Varikuti
authors.affiliation: Hematology Oncology; Blood and Marrow Transplant Program; Nationwide Children's Hospital ; Columbus, OH USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.affiliation: Department of Internal Medicine; Division of Hematology; The Ohio State University; Columbus, OH USA; Division of Medicinal Chemistry; College of Pharmacy; The Ohio State University; Columbus, OH USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Microbiology; The Ohio State University; Columbus, OH USA; Department of Pathology; The Ohio State University Medical Center; Columbus, OH USA.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
keywords: Btk; IL-17; T cells; TLR-4; dendritic cells; ibrutinib