Abnormal glucose homeostasis and pancreatic islet function in mice with inactivation of the Fem1b gene.

Type 2 diabetes mellitus is a disorder of glucose homeostasis involving complex gene and environmental interactions that are incompletely understood. Mammalian homologs of nematode sex determination genes have recently been implicated in glucose homeostasis and type 2 diabetes mellitus. These are the Hedgehog receptor Patched and Calpain-10, which have homology to the nematode tra-2 and tra-3 sex determination genes, respectively. Here, we have developed Fem1b knockout (Fem1b-KO) mice, with targeted inactivation of Fem1b, a homolog of the nematode fem-1 sex determination gene. We show that the Fem1b-KO mice display abnormal glucose tolerance and that this is due predominantly to defective glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion is also affected. The Fem1b gene is expressed in pancreatic islets, within both beta cells and non-beta cells, and is highly expressed in INS-1E cells, a pancreatic beta-cell line. In conclusion, these data implicate Fem1b in pancreatic islet function and insulin secretion, strengthening evidence that a genetic pathway homologous to nematode sex determination may be involved in glucose homeostasis and suggesting novel genes and processes as potential candidates in the pathogenesis of diabetes mellitus.

Effects of estrogen receptor subtype-selective agonists on immune functions in ovariectomized mice.

Estrogens have multiple influences on immune functions. Estrogen receptors (ERs) have two distinct subtypes - alpha and beta. To explore the specific roles of each ER subtype in estrogen-mediated immunomodulation, we investigated the effects of ER subtype-selective agonists on immune functions in ovariectomized Balb/c mice. Treatment with ERalpha-selective agonist propyl pyrazole triol (PPT) caused thymic atrophy and significant changes in thymic CD4/CD8 phenotypic profile. In contrast, ERbeta-selective agonist diarylpropionitrile (DPN) alone had no effect on thymic weight, cellularity or CD4/CD8 phenotype expression. When coadministered with PPT, DPN partially antagonized PPT-evoked decrease in thymic cellularity and also partially attenuated PPT-induced shifts in thymic T-cell phenotype. These results indicate that ERalpha plays a predominant role in estrogen-induced thymic atrophy and ERbeta activation may partially down-regulate ERalpha-mediated effects on thymic cellularity and T-cell phenotype expression. In addition, PPT administration induced a reduction in the percentage of mature B cells in the spleen, and enhanced IFN-gamma production but suppressed IL-6 production from in vitro Con A-stimulated splenocytes as estradiol (E(2)) did, whereas DPN treatment had no effects either alone or with PPT, suggesting ERalpha mediates these estrogen actions. Treatment with PPT or DPN did not augment anti-DNP antibody production after DNP-KLH immunization as E(2) did, implying that not merely one ER signaling pathway is involved in mediating estrogen's effects on specific humoral immune responses. Our study further indicates ER subtype-selective agonists provide a novel approach to explore each ER subtype-mediated immunomodulation.

Cox-2 inhibitors: today and tomorrow.

The elucidation of inducible cyclooxygenase (Cox-2) dependent inflammatory pathways led to the development of specific Cox-2 inhibitors, the coxibs. These agents include the currently available celecoxib and rofecoxib and such second-generation agents as parecoxib, valdecoxib, and etoricoxib. The therapeutic advantage of coxibs is founded primarily in their lack of significant gastrointestinal (GI) side effects. Clinical trials have demonstrated the efficacy of coxibs to be completely comparable with traditional nonsteroidal anti-inflammatory drugs (NSAIDs), and pharmacoeconomics suggest favorable cost/benefit ratios with these agents compared with traditional NSAIDs, related to their reduced GI complication profiles and lower indirect costs associated with disability. Although several clinical questions remain (eg, use with low-dose aspirin, risk of thrombosis, myocardial infarction, edema, and hypertension), the emergence and clinical utility of coxibs is likely to continue on the basis of their efficacy and relative GI safety advantage. Although newer, more specific Cox-2 inhibitors may alter the choice, it is likely that this class of anti-inflammatories will become (if they have not already) the drugs of first choice in the treatment of acute pain, chronic pain, and most rheumatic conditions in the 21st century. In addition to the treatment of rheumatic conditions, it is possible that coxibs will also be of clinical utility in protection against malignant transformation and Alzheimer disease.

Mycophenolate mofetil: selective T cell inhibition.

Mycphenolate mofetil is a suppressor of T cell proliferation and adhesion. Its primary mode of action is inhibition of inosine monophosphate dehydrogenase, a purine salvage pathway required by T lymphocytes. Although the role of T cells in rheumatoid arthritis (RA) has been controversial, a preliminary report of mycophenolate mofetil's successful use in RA patients clearly suggests that its efficacious properties need further investigation. Its favorable risk/benefit ratio, a broad clinical experience in kidney transplantation, and its recent extension to other rheumatic diseases suggests that this new antirheumatic agent has significant therapeutic potential for suppression of synovial inflammation.

The pathogenesis of rheumatoid arthritis: a guide to therapy.

The cause of rheumatoid arthritis (RA) is unknown; however, extensive research has yielded great insight into its pathogenesis. Lymphocytes play a significant role, but a lesser role in the perpetuation of late disease. The rheumatoid synovium is composed primarily of fibroblasts and monocytes that produce inflammatory cytokines, of which interleukin-1 and tumor necrosis factor are of key importance. Potential regulatory mechanisms balancing the effects of these cytokines are inadequate to prevent joint damage and subsequent disability. These cytokines seem responsible for stimulating destructive processes in the joint via induction of prostaglandins, angiogenesis, chemokines, adhesion molecules, osteoclastogenesis, and matrix metalloproteinases. This review discusses recent research findings in the immunopathogenesis of RA with respect to potential targets for therapy.

Xenoestrogen modulation of the immune system: effects of dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are complex organic compounds that are frequently found in the environment as a result of agricultural and industrial activities. Both compounds have substantial immune system and endocrine system disrupting activity, acting as estrogen agonists or antagonists (xenoestrogens). Research has demonstrated that exposure to xenoestrogens can result in body weight loss, developmental abnormalities, thymic atrophy, carcinogenesis, and tissue-specific hypoplastic and hyperplastic responses. Although several studies have reported significant adverse effects of these compounds on the endocrine system, very few investigations have focused on the specific mechanisms of action on the immune system. This paper reviews the cellular and molecular mechanisms of DDT- and TCDD-induced toxicity on the endocrine and immune systems, and explores their potential impact on the pathogenesis of immune disease.

Coumestrol, bisphenol-A, DDT, and TCDD modulation of interleukin-2 expression in activated CD+4 Jurkat T cells.

Endogenous estrogens are known to modulate several components of immune response, including interleukin-2 (IL-2) production. IL-2 is a cytokine that plays an important role in adaptive immune responses. These responses may be modulated by xenoestrogens such as coumestrol, bisphenol A (BPA), DDT, and TCDD. In this research, we examined the effects and potential mechanisms of action of these estrogenic compounds on IL-2 production in activated CD4+ Jurkat T cells. IL-2 production was analyzed by ELISA and Western Blot. At the transcriptional level, protein expression was examined by RT-PCR. Coumestrol, DDT and TCDD (but not BPA) significantly suppressed IL-2 production in activated CD4+ Jurkat T cells, at the transcriptional and translational levels. The transcriptional suppression of IL-2 was associated with decreased protein levels of NF-kappabeta, an important IL-2 positive transcription factor, without affecting the expression of Ikappa-Balpha protein expression, an important inhibitor of NF-kappabeta nuclear translocation. Although the direct mechanisms of xenoestrogens modulation of the immune system remain to be elucidated, coumestrol-, DDT- and TCDD-induced suppression of IL-2 may have ramifications for our understanding of the impact of xenoestrogens on health and disease.

Molecular and cellular mechanisms associated with autoimmune diseases.

Evidence points to increases in the incidence and prevalence of several autoimmune diseases in the United States. As a result, the cost to public health from clinical management of autoimmune conditions is on the rise. The initiation and progression of autoimmune disturbances involves both genetic and environmental factors. Deficiencies in important proteins that normally participate in maintaining checks and balances within the internal milieu may render an individual prone to developing autoantibodies. Structural abnormalities or decline in normal levels of the pentraxins (serum amylase-P protein, the acute phase proteins, complement, and C-reactive proteins) have been shown to induce autoimmunity. Irregular transmission of information arising from multiple signal transduction pathways typically associated with the serine/threonine cascade routes of mitogen activating phosphorylation kinases, has also been found to induce autoimmunity. The kind of ligand/receptor interactions drives physical recruitment of different signals within the lymphocyte; these links define the quality and quantity of subsequent immune responses. CD95 or the Fas/Apo-1 and its ligand CD95L participate in regulating lymphocyte populations and therefore influence various aspects of immune responses. Mutational abnormalities resulting from synthesis of proteins by the CD95 and/or its ligand CD95L may result in alterations in the apoptotic pathways. Apoptosis may be completely inhibited, activated or partially stimulated. Modulation of apoptosis may lead to accumulation of self-antigens. Subsequently the immune system may be stimulated to react against self-molecules through lymphatic hyperplasia. This process may end up in proliferative disorders and enhanced susceptibility to autoimmune syndromes. This paper deals with mechanisms of autoimmunopathogenesis at the cellular and molecular levels. Emphasis is laid on the role of T and B cell receptor/ligand interactions, functions and malfunctions due to structural and quantitative alterations in T- B- cell clusterof antigen determinants. Genetically susceptible patients who develop spontaneous autoimmune diseases are examined and the etiological factors implicated in the initiation and subsequent dissemination of autoimmune diseases is discussed.

Effects of cyclic versus sustained estrogen administration on peripheral immune functions in ovariectomized mice.

PROBLEM: Estrogens have multiple influences on immune functions. We aimed to compare the effects of cyclic versus sustained estrogen treatments under the same accumulated dose on peripheral immune functions in ovariectomized mice. METHOD OF STUDY: Ovariectomized adult Balb/c mice were treated with estradiol (E2) by s.c. injection once every 4 days (total 44.8 microg) or by pellet implantation (total 44.2 microg). After 6 weeks of treatment, all animals were immunized with DNP-KLH. Peripheral immune functions were assessed 10 days later. RESULTS: Both cyclic and sustained E2 treatments significantly reduced the percentage of splenic B220(+)sIgM(+) cells, enhanced IFN-gamma production and suppressed IL-6 secretion from Con A-stimulated splenocytes, and increased serum anti-DNP antibody levels. No differences were found in the above responses or in uterine weight gain between the two regimens of E2 administration. CONCLUSION: There are no differential effects on peripheral immune functions between cyclic and sustained estrogen administration under the same total dose.

Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model.

The specific roles of estrogen receptor (ER) subtypes alpha and beta in mediating estrogen's influences on lupus autoimmunity are unknown. Herein we found that ovariectomized NZB/NZW F1 mice treated with propyl pyrazole triol (ERalpha-selective agonist) had significantly shorter survival, earlier development of albuminuria, higher serum concentrations of total IgG and prolactin, increased serum levels of anti-DNA IgG3, IgG2a and IgG2b and decreased anti-DNA IgG1 level compared to vehicle controls. In contrast, diarylpropionitrile (ERbeta-selective agonist) administration significantly decreased serum anti-DNA IgG2b level but did not significantly affect serum levels of other anti-DNA IgG subclasses, serum total IgG or prolactin concentration, mortality or the occurrence of albuminuria. These findings suggest that ERalpha activation plays the predominant and immunostimulatory role in estrogen-mediated modulation of lupus while ERbeta activation appears to have a slightly immunosuppressive effect on this disease. ERalpha activation coincidentally increased serum prolactin concentrations and may accelerate lupus disease activity also through this mechanism.