Inhibition of cyclic AMP response element-binding protein/cyclic AMP response element-mediated transcription by the immunosuppressive drugs cyclosporin A and FK506 depends on the promoter context.

The immunosuppressants cyclosporin A and FK506 (tacrolimus) can block the phosphatase calcineurin, thereby inhibiting gene transcription directed by the cyclic AMP (cAMP)- and calcium-responsive transcription factor, cAMP response element (CRE)-binding protein, and its binding site, CRE, in various cell lines. This action is a novel molecular mechanism of cyclosporin A and FK506 action. Because inhibition of CREB/CRE-directed transcription by cyclosporin A and FK506 has previously been observed by using synthetic minienhancers, reporter fusion genes were constructed to examine the effect of cyclosporin A and FK506 on the transcriptional activity of CRE-containing natural promoters. In transient transfection experiments, cyclosporin A and FK506 inhibited the transcriptional activation by cAMP and the membrane depolarization of three CRE-containing promoters. However, cyclosporin A and FK506 failed to inhibit the activation by cAMP of another promoter, the rat insulin I gene promoter. The lack of cyclosporin A/FK506 sensitivity is not intrinsic to the insulin CRE because cyclosporin A and FK506 inhibited the activation by cAMP of the insulin CRE when isolated and used as a synthetic minienhancer. Rather, cyclosporin A/FK506 resistance may be conferred by specific promoter interactions because a mutational analysis of the insulin promoter revealed that inside this promoter, CRE activity depends on an adjacent control element. These data show that cyclosporin A and FK506 can inhibit CRE activity when the CRE resides in its natural promoter. However, the cyclosporin A/FK506 sensitivity depends on the specific promoter context. The results suggest that cyclosporin A and FK506 may alter target tissue function through the regulation of a subset of CRE-containing genes.

[Clinical study on rheumatoid arthritis of the TMJ]. / Klinische Studie zur rheumatischen Arthritis des Kiefergelenkes.

256 individuals with inflammatory rheumatic diseases and 117 individuals of two control groups returned their questionnaires in a survey of subjective symptoms of the masticatory system. Subjective symptoms of the temporomandibular joint (tmj) were reported by 41% of the patients with rheumatoid arthritis, 29% of the patients with psoriatic arthritis, 20% of the patients with ankylosing spondylitis and 23% of the patients with other rheumatic diseases (such as Reiter's syndrome). Statistically significant differences (p less than 0.05) regarding the occurrence of "difficulties in opening the mouth wide" and "crepitus from the tmj" were found between the various types of rheumatic arthritis. In 40 patients with rheumatic diseases and tmj-symptoms the tmj was examined clinically, by orthopantomography and lateral tomography. Radiographic abnormalities were found in 68% of the patients and classified by a new radiographic index, according to the index of Steinbrocker. There were no indications for a relationship between a loss of posterior support and extensive radiographic changes of the tmj. The most common objective symptoms were pain on chewing, crepitus in the tmj and tenderness to palpation of the masticatory muscles and neck.