Cigarette smoke condensate extracts induce IL-1-beta production from rheumatoid arthritis patient-derived synoviocytes, but not osteoarthritis patient-derived synoviocytes, through aryl hydrocarbon receptor-dependent NF-kappa-B activation and novel NF-kappa-B sites.

Cigarette smoking is a major established environmental risk factor for rheumatoid arthritis (RA), and synoviocyte-derived proinflammatory cytokines are implicated in the pathogenesis of RA. We have reported that aryl hydrocarbon or cigarette smoke condensate (CSC) is able to upregulate the production of proinflammatory cytokines from an RA patient-derived synovial fibroblast cell line MH7A. In this study, we compared the effect of CSC on induction of interleukin-1ß (IL-1ß) from RA or osteoarthritis (OA) patient-derived synovial fibroblasts, and studied the mechanism of the effect of CSC. CSC induced IL-1ß mRNA from RA patient-derived synoviocytes and MH7A, but not from OA patient-derived synoviocytes. CSC induced the mRNA and both precursor and mature forms of IL-1ß, and caspase-1 activity in MH7A. The mechanism of CSC-induced IL-1ß mRNA expression was investigated in MH7A. Reporter gene analyses and promoter pull-down assay indicated that 3 novel NF-κB sites at -3771 to -3762 bp, -3105 to -3096 bp, and -2787 to -2778 bp in the promoter region of the IL-1ß gene, especially the far distal NF-κB site and NF-κB activation, are critical for the gene activation by CSC. CSC-induced NF-κB activation, IL-1ß promoter activity, IL-1ß mRNA upregulation, and CYP1A1 mRNA induction were all inhibited by an aryl hydrocarbon receptor (AhR) antagonist α-naphthoflavone. These results indicate that CSC induced IL-1ß production from RA patient-derived synoviocytes, but not OA patient-derived synoviocytes, through AhR-dependent NF-κB activation and novel NF-κB sites.

Etiological role of cigarette smoking in rheumatoid arthritis: Nasal exposure to cigarette smoke condensate extracts augments the development of collagen-induced arthritis in mice.

Cigarette smoking is a major environmental risk factor for rheumatoid arthritis (RA). However, the experimental bases supporting the etiological role of cigarette smoking in RA have not been fully provided. We have reported that cigarette smoke condensate (CSC), by means of subcutaneous injection into DBA/1J mice with collagen and complete Freund's adjuvant or intraperitoneal injection one day before immunization, augmented the development of arthritis in the mouse model of collagen type II-induced arthritis (CIA). However, these experimental procedures may not be appropriate for cigarette smoking. In this study, we nasally exposed mice to mainstream CSC and found that CSC augmented the induction and development of arthritis and antibody level against collagen. Histological examination confirmed the augmenting effect of CSC. These findings provide experimental bases supporting the etiological role of cigarette smoking in RA.

Formation of embryoid bodies by mouse embryonic stem cells on plastic surfaces.

Mouse embryonic stem (ES) cells were cultured on artificial polymeric biomembranes with a phospholipid polymer (phosphatidylcholine, PC) surface. ES cells aggregated to form an embryoid body (EB) on the PC surface immediately after seeding. Single EBs formed on the PC surface after 3 d, and their size was depended on the initial number of cells that were seeded. In contrast, many small EBs with a nonuniform shape formed on a conventional hydrophobic nontreated polystyrene surface. RT-PCR assays of the EBs indicated that cell-cell interactions were enhanced in EBs that formed on the PC surface compared with EBs that formed on the polystyrene surface. The transcription factor Pax6, which is a marker of the differentiation of ES cells to neurons, was not expressed in EBs that formed on the PC surface; however, EBs that formed on the polystyrene surface did express Pax6, indicating that they were undergoing differentiation into neurons. When stimulated with retinoic acid (an inducer of differentiation into neurons), EBs on the PC surface expressed Pax6. We also observed that the adhesion of ES cells to the PC surface was reduced. Thus, the formation of large EBs on the PC surface was due to enhanced cell-cell interaction and inhibition of nonspecific differentiation to neurons.