Reduction of left ventricular hypertrophy by sirolimus in kidney transplant recipients: a nonrandomized clinical trial

Persistence of left ventricular hypertrophy [LVH] in renal transplant recipients is associated with unfavorable outcomes. Calcineurin-inhibitor [CNI] nephrotoxicity is a major cause of morbidity and mortality after kidney transplantation. In this study we compared sirolimus [SRL] with calcineurin-inhibitor as primary immunosuppressants for the attenuation of left ventricular hypertrophy in renal transplantation recipients. In this prospective cohort study done in Shariati Hospital in 2010, we evaluated the effects of sirolimus and CNI on LVH of 55 renal transplant recipients. The cases [19] received sirolimus while the controls [36] received CNI while being matched for age and duration of transplantation. Data regarding blood pressure [BP], hemoglobin, serum creatinine, uric acid and lipid concentrations were assessed and changes in left ventricular [LV] mass were evaluated by echocardiography over a one-year follow-up. Left ventricular mass significantly decreased [P=0.0001] in the SRL group but blood pressure did not differ between the two groups. LV mass and LV mass index both decreased significantly [P<0.05] but the difference was not associated with changes in BP. The difference in interventricular septal thickness at end diastole [IVSD] and posterior wall diameter [PWD] were significant [P<0.05] in the SRL group but the difference in end diastolic diameter [EDD] was not significant. Conversion from CNI to SRL-based immunosuppressive therapy in RTRs is safe and SRL may decrease LVH. SRL seems to be safe and improve renal function without cardiac compromise in kidney transplant recipients

Immunosuppressive effects of rifampicin on a tuberculosis patient after renal transplant

Rifampicin is a semisynthetic derivative of rifamycin B and inhibits the growth of a variety of bacteria. Rifampicin causes an increase in corticosteroid clearance, and a decrease in the blood concentrations of calcineurin inhibitors by inducing Cytochrome P[450] 3A4 in the liver. It is generally acknowledged that a substantial increase in the dosage of calcineurin inhibitors is required to achieve the efficacious target concentrations and avoid graft rejection. We report a case of patient who received a living-related donor renal transplant with stable renal function during the rifampicin based anti-tuberculosis treatment, even the blood concentration of tacrolimus [FK506] decreased. Interestingly, acute rejection was observed at the end of anti-tuberculosis treatment, even the blood concentration of FK506 was reduced to target level

Is mycophenolate more than just an immunosuppressant?--An overview.

The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.

Management of steroid resistant nephrotic syndrome.

JUSTIFICATION: There is a lack of evidence based guidelines for management of children with steroid resistant nephrotic syndrome (SRNS). PROCESS: Experts of the Indian Society of Pediatric Nephrology were involved in a two-stage process, the Delphi method followed by a structured face to face meeting, to formulate guidelines, based on current practices and available evidence, on management of these children. Agreement of at least 80% participants formed an opinion. OBJECTIVES: To develop specific, realistic, evidence based criteria for management of children with idiopathic SRNS. RECOMMENDATIONS: The Expert Group emphasized that while all patients with SRNS should initially be referred to a pediatric nephrologist for evaluation, the subsequent care might be collaborative involving the primary pediatrician and the nephrologist. Following the diagnosis of SRNS (lack of remission despite treatment with prednisolone at 2 mg/kg/day for 4 weeks), all patients (with initial or late resistance) should undergo a renal biopsy, before instituting specific treatment. Patients with idiopathic SRNS secondary to minimal change disease or focal segmental glomerulosclerosis should receive similar therapy. Effective regimens include treatment with calcineurin inhibitors (tacrolimus, cyclosporine), intra-venous cyclophosphamide or a combination of pulse corticosteroids with oral cyclophosphamide, and tapering doses of alternate day corticosteroids. Supportive management comprises of, when indicated, therapy with angiotensin converting enzyme inhibitors and statins. It is expected that these guidelines shall enable standardization of care for patients with SRNS in the country.

Down syndrome critical region 1 enhances the proteolytic cleavage of calcineurin

Down syndrome critical region 1 (DSCR1), an oxidative stress-response gene, interacts with calcineurin and represses its phosphatase activity. Recently it was shown that hydrogen peroxide inactivates calcineurin by proteolytic cleavage. Based on these facts, we investigated whether oxidative stress affects DSCR1-mediated inactivation of calcineurin. We determined that overexpression of DSCR1 leads to increased proteolytic cleavage of calcineurin. Convertsely, knockdown of DSCR1 abolished calcineurin cleavage upon treatment with hydrogen peroxide. The PXIIXT motif in the COOH-terminus of DSCR1 is responsible for both binding and cleavage of calcineurin. The knockdown of overexpressed DSCR1 in DS fibroblast cells also abrogated calcineurin proteolysis by hydrogen peroxide. These results suggest that DSCR1 has the ability to inactivate calcineurin by inducing proteolytic cleavage of calcineurin upon oxidative stress.

Sirolimus en trasplante de órgano sólido pediátrico: Experiencia en 5 casos / Use of Sirolimus in five pediatric patients undergoing solid organ transplantation

Sirolimus (SRL) is an immunosuppressive drug increasingly used in children undergoing solid organ transplantation. SRL does not cause glucose intolerance, hypertension, nephrotoxicity or neurotoxicity offering significant potential advantages over calceneurin inhibitors (CM). Aim: To report five children treated with SRL. Material and methods: A retrospective review of four children undergoing orthotopic liver transplantation (OLT) and one undergoing renal transplantation with recurrent acute rejection (RAR), chronic rejection (CR) or toxicity due to CM, treated with SRL between June 2001 and November 2006. Results: As primary immunosuppressive therapy, all patients received 3 drugs: CM (Tacrolimus (FK) or Cyclosporine), mycophenolate mofetil and steroids. Mean age at treatment with SRL was 98 months. Children undergoing OLT had a ¡ate introduction of SRL (mean time after OLT: 37 months), and mean follow-up was 24 months. In this group rescue indications of SRL were RAR in one, CR in one, thrombotic thrombocytopenic purpura (TTP) in one, food allergy in one and other CM toxicity in three. Only one did not experience adverse events due to SRL, but no one required discontinuation of SRL. There were remissions of RAR, CR, TTP and food allergy. The patient with RT was switched from FK to SRL at day 18th after RT, but he had severe neutropenia that led to discontinuation of SRL. Conclusions: SRL may be useful in pediatric solid organ transplant recipients suffering from RAR, CR, TTP, food allergy and CM toxicity. Careful attention should be directed to detect side effects and avoid severe complications.

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1 percent, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20 percent (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3 percent) and cytomegalovirus disease (4.3 percent) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.

Calcineurin inhibitors in the treatment of allergic dermatitis

OBJETIVO: Revisar o papel dos inibidores da calcineurina no tratamento das dermatoses alérgicas, com ênfase nos mecanismos de ação, eficácia e efeitos adversos tópicos e sistêmicos. FONTES DOS DADOS: Artigos de língua inglesa publicados na MEDLINE, considerando as palavras chave: pimecrolimus, tacrolimo, calcineurin inhibitors. Foram selecionados os artigos originais que apresentaram estudos controlados e estudos abertos para avaliação da eficácia, tolerabilidade e eventos adversos. Também foram avaliados artigos de revisão e relatos e série de casos, sendo estes últimos considerados apenas para avaliação de efeitos adversos. Foram consultados os sites oficiais da Food and Drug Administration e dos fabricantes de inibidores da calcineurina. SíNTESE DOS DADOS: Os dados mostraram que inibidores de calcineurina são eficientes no tratamento da dermatite atópica leve a grave, levando a melhora dos sintomas, diminuição do número de crises e necessidade de corticoterapia tópica. Apresentam boa tolerabilidade e poucos efeitos adversos tópicos. Até o momento, não há evidências que sustentem a maior prevalência de neoplasias nos pacientes que utilizam esses medicamentos; entretanto, um adequado sistema de farmacovigilância está montado para avaliar esse aspecto. CONCLUSÕES: Os inibidores de calcineurina são uma nova classe de medicamentos para o tratamento das dermatoses alérgicas. São eficazes, tolerados e com poucos efeitos adversos. Devem ser sempre utilizados de acordo com as orientações preconizadas, e os pacientes devem ser sempre acompanhados pelo médico durante e após sua administração.

OBJECTIVE: To review the role of calcineurin inhibitors in the treatment of allergic dermatitis, focusing on mechanisms of action, efficacy and topical and systemic adverse effects. SOURCES: Articles written in English and published in MEDLINE using the following keywords: pimecrolimus, tacrolimus, calcineurin inhibitors. Original articles that presented controlled and open studies for assessing efficacy, tolerability and adverse effects were selected. Review articles and case series were also evaluated; the latter was only considered for assessing adverse effects. The official websites of the Food and Drug Administration and of manufacturers of calcineurin inhibitors were also used. SUMMARY OF THE FINDINGS: The data showed that calcineurin inhibitors are efficient in the treatment of mild to severe atopic dermatitis, leading to improvement in symptoms, reduction in number of attacks and need of topical corticotherapy. Calcineurin inhibitors have good tolerability and few topical adverse effects. To date, there has been no evidence to support higher prevalence of neoplasia in patients using these drugs; however, an adequate pharmacovigilance system has been set up to assess this aspect. CONCLUSIONS: Calcineurin inhibitors, which are a new drug class in the treatment of allergic dermatitis, are efficient, well tolerated and have few adverse effects. Calcineurin inhibitors should always be used according to recommended guidelines, and patients should always be followed by the physician during and after their administration.

Cyclosporin-A does not affect skeletal muscle mass during disuse and recovery

Cyclosporin-A (CsA) is an immunosuppressive drug that acts as an inhibitor of calcineurin, a calcium phosphatase that has been suggested to play a role in skeletal muscle hypertrophy. The aim of the present study was to determine the effect of CsA administration (25 mg kg-1 day-1) on skeletal muscle mass and phenotype during disuse and recovery. Male Wistar rats received vehicle (N = 8) or CsA (N = 8) during hind limb immobilization (N = 8) and recovery (N = 8). Muscle weight (dry/wet) and cross-sectional area were evaluated to verify the effect of CsA treatment on muscle mass. Muscle phenotype was assessed by histochemistry of myosin ATPase. CsA administration during immobilization and recovery did not change muscle/body weight ratio in the soleus (SOL) or plantaris (PL). Regarding muscle phenotype, we observed a consistent slow-to-fast shift in all experimental groups (immobilized only, receiving CsA only, and immobilized receiving CsA) as compared to control in both SOL and PL (P < 0.05). During recovery, no difference was observed in SOL or PL fiber type composition between the experimental recovered group and recovered group receiving CsA compared to their respective controls. Considering the muscle/body weight ratio, CsA administration does not maximize muscle mass loss induced by immobilization. Our results also indicate that CsA fails to block skeletal muscle regrowth after disuse. The present data suggest that calcineurin inhibition by CsA modulates muscle phenotype rather than muscle mass.

Impact of initial exposure to calcineurin inhibitors on kidney graft function of patients at high risk to develop delayed graft function

We conducted a retrospective analysis of the influence of full doses of calcineurin inhibitors [8-10 mg kg-1 day-1 cyclosporine (N = 80), or 0.2-0.3 mg kg-1 day-1 tacrolimus (N = 68)] administered from day 1 after transplantation on the transplant outcomes of a high-risk population. Induction therapy was used in 13 percent of the patients. Patients also received azathioprine (2 mg kg-1 day-1, N = 58) or mycophenolate mofetil (2 g/day, N = 90), and prednisone (0.5 mg kg-1 day-1, N = 148). Mean time on dialysis was 79 ± 41 months, 12 percent of the cases were re-transplants, and 21 percent had panel reactive antibodies >10 percent. In 43 percent of donors the cause of death was cerebrovascular disease and 27 percent showed creatinine above 1.5 mg/dL. The incidence of slow graft function (SGF) and delayed graft function (DGF) was 15 and 60 percent, respectively. Mean time to last dialysis and to nadir creatinine were 18 ± 15 and 34 ± 20 days, respectively. Mean creatinine at 1 year after transplantation was 1.48 ± 0.50 mg/dL (DGF 1.68 ± 0.65 vs SGF 1.67 ± 0.66 vs immediate graft function (IGF) 1.41 ± 0.40 mg/dL, P = 0.089). The incidence of biopsy-confirmed acute rejection was 22 percent (DGF 31 percent, SGF 10 percent, IGF 8 percent). One-year patient and graft survival was 92.6 and 78.4 percent, respectively. The incidence of cytomegalovirus disease, post-transplant diabetes mellitus and malignancies was 28, 8.1, and 0 percent, respectively. Compared to previous studies, the use of initial full doses of calcineurin inhibitors without antibody induction in patients with SGF or DGF had no negative impact on patient and graft survival.

Inmunosupresión para receptores de trasplante renal: estrategias actuales / Immunosuppression for kidney transplant recipients: current strategies

Immunosuppressive therapy aims to protect transplanted organs from host responses. The success achieved during the last two decades in patient and graft survival is mainly related to the development and clinical use of efficacious immunosuppressive drugs. Nevertheless, the challenge of achieving a balance of adequate graft protection while minimizing the adverse consequences of excessive immunosuppression in the long-term continues. Current maintenance immunosuppression for renal transplant recipients generally consists of a calcineurin inhibitor plus an adjunctive antiproliferative agent, and steroids. The addition of induction therapy with a variety of monoclonal or polyclonal antibodies provides a more potent immunosuppression and its use is more relevant in patients with a high immunological risk. More recently, mammalian target of rapamycin inhibitors have been incorporated in different schemes proven its efficacy in a number of protocols. The incidence of acute rejection is now in its lower historical percentage and excellent results are reported from many transplant centers all over the world due mainly to a judicious combination of these drugs evaluated through many clinical studies. However, long-term use of immunosuppressive drugs convey inherent risks which translate in an increase of cancers and infections, among others. Ongoing investigations and clinical protocols involving new immunosuppressive drugs and biological agents are yielding important information on how to obtain tolerance or the nearest to this goal. Furthermore, there should be a continuous improvement in patient and graft survival, as the use of different immunosuppressive agents for induction and maintenance are individualized (adapted to each patient).

La terapia inmunosupresora empleada en receptores de trasplante tiene el objetivo de proteger el injerto de la respuesta inmunoloógica generada por parte del huésped. El éxito logrado en el transcurso de las últimas dos décadas en la supervivencia de receptores e injertos, ha dependido en gran medida del desarrollo y uso clínico de fármacos inmunosupresores de probada eficacia. Empero el enorme beneficio que han representado, el reto continúa para mantener un balance adecuado entre la protección inmunológica del injerto y la minimización de las consecuencias adversas derivadas de su indispensable utilización a largo plazo. La terapia inmunosupresora actual de mantenimiento en receptores de trasplante renal consiste habitualmente en la administración de un inhibidor de calcineurina, un agente antiproliferativo, como adyuvante, y esteroides. La adición de terapia de inducción, con modalidades biológicas de anticuerpos mono o policlonales, proveen un mayor grado de inmunosupresión y su empleo adquiere gran relevancia en pacientes con mayor riesgo inmunológico. En una etapa más reciente, los inhibidores del blanco de rapamicina han sido introducidos en varios esquemas después de probar su eficacia en múltiples protocolos. La incidencia de rechazo agudo ha alcanzado sus más bajos índices históricos y los resultados alcanzados en muchos centros de trasplante del mundo son excelentes, derivados en gran medida de la combinación juiciosa de estos fármacos, evaluados en una gran variedad de estudios. El empleo crónico de estos fármacos conlleva riesgos inherentes que se traducen en riesgos incrementados para el desarrollo de infecciones y neoplasias, entre otros. Así, mientras esperamos nuevos avances derivados de una gran profusión de estudios de investigación y protocolos clínicos con nuevas drogas inmunosupresoras y compuestos biológicos, encaminados a obtener tolerancia o lo más cercano a este propósito, deberemos ser capaces de continuar mejorando la vida funcional de la mayoría de los injertos y, desde luego, de sus receptores, "individualizando" (de acuerdo con los riesgos de cada paciente) el empleo de los agentes inmunosupresores disponibles para inducción y mantenimiento.

Avances en inmunosupresión en trasplante hepático / Advances in immunossuppression in liver transplantation

The history of Immunosuppresslon is a long one. From the utilization of steroids and azathloptlne In the 50's to the design of humanized molecules that specifically block cell surface receptors. Liver transplantation is one of the procedures that benefit the most with the development of new immunosuppressors and is also one of the reasons to create a new branch in research and clinical practice: transplant medicine. It also set the standards for research in the "immunologic tolerance" field. The cornerstone in the post-liver transplant stage is the utilization of calcineurin inhibitors combined with new anti-metabolites and monoclonal antibodies. All these settings conforms a promising field in the research of new and better immunosuppressing agents.

Se ha recorrido mucho camino desde el diseño de la inmunosupresión en la década de los 50's. Desde la utilización de los esteroides y la azatioprina hasta el desarrollo de moléculas humanizadas, que bloquean específicamente receptores de superficie celular para inducir tolerancia del injerto, ha transcurrido medio siglo. El trasplante hepático ha sido uno de los procedimientos más beneficiados con el desarrollo de las nuevas drogas inmunosupresoras y ha dado origen a una nueva rama de la medicina: la medicina de trasplantes. También ha sentado las bases de investigación tendiente a lograr la "tolerancia inmunológica" del órgano trasplantado. La piedra angular en la inmunosupresión postrasplante hepático es la utilización de los inhibidores de calcineurina que, en combinación con nuevos antimetabolitos y anticuerpos monoclonales, dibujan un futuro promisorio en la búsqueda de mejores agentes.

Acción novedosa de la aldosterona en la nefrotoxicidad por ciclosporina / Novel action of aldosterone in CsA nephrotoxicity

Calcineurin inhibitors are helpful ímmunosuppressíve agents in clinical practice. Thanks to their lower cost respect with new ímmunosuppressíve therapy, calcineurin inhibitors in our country continue being the most used treatment in solid organ transplant recipients or patients with autoimmune disease. In the 80's decade cyclosporine A (CsA) was introduced as the first calcineurin inhibitor transforming the immunosuppression therapy. Up to date, many articles evaluating beneficial and adverse effects of CsA have been published. In this review, basic aspects and actions of CsA are analyzed together with studies from our laboratory that pointed out the pathophysiological role of aldosterone as a mediator of functional and structural changes that are observed in CsA nephrotoxicity. Based in our findings, we proposed that in CsA nephrotoxicity, the aldosterone mediates renal vasoconstriction and enhances TGFJ3 expression promoting the development of nefrotoxicity. Finally, results from our laboratory and others allow us to suggest that aldosterone receptors blockade with spironolactone or eplerone could be a pharmacological therapy to reduce or prevent acute and chronic CsA nephrotoxicity in transplant recipients.

Los inhibidores de calcineurina son los agentes inmunosupresores más potentes con los que se cuenta en la práctica clínica, y gracias a su bajo costo respecto a las nuevas terapias inmunosupresoras, en nuestro país continúan siendo los agentes terapéuticos más utilizados para el manejo de pacientes con enfermedades autoinmunes o que reciben trasplantes. En la década de los 80's se introdujo la ciclosporina A (CsA) como primer inhibidor de calcineurina, lo cual revolucionó la terapia inmunosupresora. Desde entonces se han publicado muy variados artículos donde se han evaluado los efectos benéficos y deletéreos de estos inhibidores; específicamente nos enfocaremos a revisar las acciones de CsA y, en particular, los resultados de nuestro laboratorio que muestran el papel fisiopatológico que juega la aldosterona como mediador de los cambios funcionales y estructurales que se observan en la nefrotoxicidad por ciclosporina. Específicamente su participación en promover la vasoconstricción renal asociada a CsA y en el desarrollo de fibrosis al inducir la expresión de TGFβ. Por lo tanto, nuestros resultados y los de otros autores nos permiten proponer el bloqueo de los receptores de aldosterona con espironolactona o eplerone como un tratamiento farmacológico útil para reducir la incidencia de nefrotoxicidad aguda y crónica, inducida por CsA en pacientes con enfermedades autoinmunes o que reciben trasplante de órganos.

A Pilot Study of Calcineurin Inhibitors (CNIs) and Steroid Avoidance Immunosuppressive Protocol among Living Donor Kidney Transplant Recipients

Calcineurin Inhibitors (CNIs) and Corticosteroids have been the main immunosuppressive agents in solid organ transplantation. Many studies have confirmed the positive impacts of withdrawal/avoidance of these agents, separately, on their side effect profiles. A pilot study was performed avoiding both agents among low-immunological-risk living donor kidney transplant recipients at a single center. Seventeen recipients were maintained on the double avoidance protocol during the study period beginning July 2002 through December 2003. Three rejection episodes occurred (out of ten) among related donor kidney recipients and six episodes (out of seven) among unrelated donor kidney recipients. Although most of the rejections were reversed with a short course of corticosteroids, the protocol was revised to exclude the unrelated donor kidney recipients. There were higher incidences of wound complications among recipients who received the initial loading dose of Sirolimus. Double avoidance of CNIs and corticosteroids is possible in living donor kidney transplant recipients with an acceptable incidence of rejection. Proper management of the side effects of Sirolimus could further minimize the incidence of rejection. A multi-center randomized study is recommended in order to recognize the benefits of avoiding CNIs and corticosteroids in renal transplant recipients.

Induction of fibronectin gene expression by inhibitors of protein phosphatase type 2B in normal and transformed fibroblasts

Two intracellular signal pathways mediated by cAMP and protein kinase C (PKC) were involved in the regulation of FN gene expression (Lee et al., Exp. Mol. Med. 30: 240, 1998). In this study, a possible involvement of protein phosphatase-dependent pathways in the regulation of FN gene expression was investigated by using protein phosphatase type 2B (PP2B) inhibitors, cyclosporin A and ascomycin. Both cyclosporin A and ascomycin increased the levels of FN mRNA in WI-38 human lung fibroblasts and the SV40-transformed WI-38 cells but not in MC3T3-E1 osteoblasts. The expression of FN appears to increase from six hours up to 48 hours after treatment suggesting that it is not an immediate effect. In addition, this effect required a new protein synthesis. Neither cyclosporin A nor ascomycin affects the phorbol myristate acetate (PMA)-induced stimulation of FN gene expression and the same result occurred in vice versa suggesting the mechanism of PMA and cyclosporin A/ascomycin in the regulation of FN gene expression may share a common downstream pathway. Taken together, this study suggests that PP2B is involved in the regulation of FN gene expression in normal and transformed fibroblasts but not in osteoblasts.