Objective. To investigate the activation and expression of CCAAT/enhancer-binding proteins (C/EBP), especially C/EBP and -␦, in rheumatoid synovium, and their pathogenic implications in rheumatoid arthritis (RA). Methods. The activation of C/EBP and -␦ was assessed in synovial tissues from patients with RA by electrophoretic mobility shift assay (EMSA); DNA binding activity of C/EBPs was evaluated by measuring EMSA band density. The expression and distribution of C/EBP and -␦ in synovial tissues were examined by immunohistochemistry analysis. As a control, synovial tissues from patients with osteoarthritis (OA) were studied. Results. Enhanced DNA binding activity of C/EBP and -␦, 2 major members of the C/EBP family, was detected in synovial tissues from RA patients, while synovial tissues from the patients with OA showed only faint or marginal activity (mean ؎ SEM arbitrary units [AU] RA 23.3 ؎ 11.7 in RA versus 4.5 ؎ 1.3 in OA; P < 0.05). Moreover, the binding activities of the C/EBP proteins were correlated with both serum C-reactive protein levels (r ؍ 0.62, P < 0.05) and synovial interleukin-6 messenger RNA levels (r ؍ 0.60, P < 0.05). In immunohistochemistry studies, C/EBP and -␦ were detected predominantly in the rheumatoid synovial lining cells (both CD14؉ and CD14؊ cells). Conclusion. C/EBP and -␦ may contribute to the pathology of rheumatoid synovitis.
CCAAT/enhancer-binding proteins (C/EBP) are a family of leucine zipper transcription factors involved in the regulation of various aspects of cellular differentiation and function in multiple tissues. These proteins dimerize through a leucine zipper by which they form homo-or heterodimers with other family members and bind to a consensus DNA motif through an adjacent basic region. Six members of the family (C/EBP␣-) have been isolated and characterized. Among them, C/EBP and -␦ are thought to be mainly involved in inflammation and immunity. Indeed, C/EBP binding motifs have been identified in the functional regulatory regions of various genes expressed by myelomonocyte-lineage cells, including those encoding the proinflammatory cytokines (interleukin-6 [IL-6], IL-1, and tumor necrosis factor ␣), other cytokines (IL-8, IL-12), cyclooxygenase 2, inducible nitric oxide synthase, collagenase 1, and intercellular adhesion molecule 1 (1). These gene products are considered to play important roles in the pathophysiology of rheumatoid arthritis (RA). Thus, C/EBPs, especially C/EBP and -␦, possibly contribute to the pathogenesis of RA. In the present study, to investigate the involvement of C/EBPs, and in particular C/EBP and -␦, in the pathogenesis of RA, we examined the activation and expression of C/EBPs in rheumatoid synovial tissue.