title: Impaired Akt Phosphorylation in Monocytes of Patients with Rheumatoid Arthritis.
abstract: It has been proposed that the Akt kinase pathway provides a regulatory mechanism to limit the inflammatory response. We examined the activation of Akt upon lipopolysaccharide (LPS) challenge in monocytes of patients with rheumatoid arthritis (RA) and correlated it with disease activity. Twelve subjects with recent-onset, DMARD-naïve RA, thirteen patients with chronic, DMARD therapy-non-responding RA and 27 healthy volunteers provided whole blood samples for phosphospecific flow cytometric measurement of unstimulated and LPS-stimulated Akt phosphorylation at serine 473 in monocytes, determined in relative fluorescence units (RFU). Activation capability, that is responsiveness of monocytes, was determined as the difference between stimulated and unstimulated samples and compared between groups using Mann-Whitney test. CRP and ESR, swollen and tender joint counts, patients' global assessment of disease activity, DAS28 score and plasma IL-6 determined by ELISA were correlated with Akt activation using Spearman method. Median (interquartile range) Akt activation capability was significantly lower in DMARD-naïve (379 RFU [285, 432], P = 0.016) and even lower in DMARD-non-responding RA (258 RFU [213, 338], P < 0.001), compared to healthy controls (505 RFU[408, 639]) and showed a negative correlation with swollen joint count (r = -0.48, CI -0.78 to -0.05, P = 0.014), CRP (r = -0.42, CI -0.80 to -0.02, P = 0.039) and plasma IL-6 levels (r = -0.44, CI -0.65 to -0.17, P = 0.001). In conclusion, Akt activation capability of monocytes is low in early untreated RA and even lower in chronic, DMARD-non-responding RA, suggesting a role for Akt pathway in the pathogenesis of RA.
authors.affiliation: Bacteriology and Immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Kuuliala
authors.affiliation: Bacteriology and Immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Kuuliala
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Hämäläinen
authors.affiliation: Rheumatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Koivuniemi
authors.affiliation: Primary Health Care and General Practice, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.|Unit of Primary Health Care, Kuopio University Hospital, Kuopio, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Kautiainen
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Moilanen
authors.affiliation: Bacteriology and Immunology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Repo
authors.affiliation: Rheumatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Leirisalo-Repo
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018501:Antirheumatic Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt