title: The role of cell type-specific responses in IFN-β therapy of multiple sclerosis.
abstract: The mechanism of IFN-β therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-β by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-κB in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-β1a or stimulation in vitro. Induction of cell-surface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-κB in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-β depends on the activation of p38 and NF-κB as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-κB and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-β therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-α/β in hepatitis and cancer.
authors: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Joana A
authors: JA
authors: Zula
authors: Holly C
authors: HC
authors: Green
authors: Richard M
authors: RM
authors: Ransohoff
authors: Richard A
authors: RA
authors: Rudick
authors: George R
authors: GR
authors: Stark
authors: Anette H H
authors: AH
authors: van Boxel-Dezaire
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016899:Interferon-beta; D048051:p38 Mitogen-Activated Protein Kinases