Peroxisome proliferator-activated receptor (PPAR ), a fatty acid-activated nuclear receptor, is implicated in adipocyte differentiation and insulin sensitisation. In view of the association of dietary fat intake and bowel disease, the expression of PPAR in rodent and human intestine was studied. Expression of PPAR mRNA was examined by Northern blot hybridisation, RNase protection, and/or competitive RT-PCR assays, whereas PPAR protein levels were evaluated by immunoblotting and immunohistochemistry. PPAR mRNA and protein were abundantly expressed in colon relative to the small intestine both in rodents and in man. Interestingly, expression of PPAR was primarily localised in the more differentiated epithelial cells in the colon. The level of expression of PPAR in colon was similar to the levels seen in adipose tissue. Expression of PPAR increased from proximal to distal segments of the colon in man. In Caco-2 and HT-29 human adenocarcinoma cells, PPAR expression increased upon differentiation, consistent with PPAR being associated with a differentiated epithelial phenotype. High-level expression of PPAR was observed in the colon, but not in the small intestine, suggesting a potential role of this nuclear receptor in the colon.
Objective. Weekly low-dose methotrexate (MTX) remains the mainstay of second-line therapy for rheu-matoid arthritis (RA). We have previously reported that adenosine, acting at specific receptors on inflammatory cells, mediates the antiinflammatory effects of MTX in both in vitro and in vivo models of acute inflammation, but the mechanism by which MTX suppresses the chronic inflammation of arthritis remains controversial. The present study was undertaken to further investigate the means by which adenosine mediates the antiinflammatory effects of MTX. Methods. The effects of 2 nonselective adenosine receptor antagonists, theophylline and caffeine, were examined, using the rat adjuvant arthritis model of RA. These agents were given alone and in conjunction with MTX, and arthritis severity was assessed clinically, radiologically, and histologically. Since rodent adeno-sine A 3 receptors are not blocked by theophylline, selective A 1 , A 2A , and A 2B receptor antagonists were tested as well. Results. Control animals developed severe arthritis , which was markedly attenuated by weekly treatment with MTX (0.75 mg/kg/week). Neither theophylline alone nor caffeine alone (each at 10 mg/kg/day) significantly affected the severity of the arthritis, but both agents markedly reversed the effect of MTX as measured by a severity index, hindpaw swelling, and hind-paw ankylosis. Radiographic and histologic analyses confirmed these observations. Neither A 1 , A 2A , nor A 2B receptor antagonists affected the capacity of MTX to ameliorate inflammation in adjuvant arthritis. Conclusion. These results provide strong evidence that adenosine mediates the antiinflammatory effects of MTX in this model of RA. Moreover, the findings suggest that abstinence from caffeine, a ubiquitous food additive and medication, may enhance the therapeutic effects of MTX in RA. Low-dose, intermittently administered metho-trexate (MTX) is among the most widely used forms of therapy for inflammatory arthritis (particularly rheuma-toid arthritis [RA]), psoriasis, and inflammatory bowel disease. MTX was introduced for the treatment of inflammatory diseases, with very little understanding of its mechanism of action. We, and subsequently others, have reported that the antiinflammatory actions of MTX are mediated by its capacity to increase extracellular adenosine concentrations (1-4). However, the studies reported to date have demonstrated that adenosine is responsible for the antiinflammatory actions of MTX only in acute inflammation; the mechanism of action of MTX in the treatment of chronic inflammation has not been fully explored.
Thiazolidinedione (TZD) insulin sensitizers are specific agonists of peroxisome proliferator activated receptor (PPAR)gamma. However, their mechanism of action and the in vivo target tissue(s) that mediate insulin sensitization remain poorly defined. Although PPARgamma messenger RNA expression has been reported in skeletal muscle, the expression of PPARgamma within myocytes in intact muscle tissue has not been examined. An antipeptide PPARgamma antibody was generated; immunohistochemistry was then used to demonstrate that PPARgamma is present within nuclei of myocytes [in both skeletal (white and red fibers) and cardiac tissue (rodent and human)]. The effect of insulin sensitizer treatment on muscle insulin action was studied using ob/ob mice after 4 days dosing with a potent (6 nM PPARgamma Kd) TZD (10 mg/kg x day). 2-deoxyglucose (2-DOG) uptake was then assessed in freshly isolated soleus muscles from lean vs. ob/ob vs. TZD-treated ob/ob mice. In lean mouse muscles, 2-DOG uptake was stimulated by 82%, 95%, 165% (with 25, 100, 2000 microU/ml insulin); muscles from ob/ob were severely insulin resistant (<80% stimulation with 2000 microU/ml insulin). Muscles from TZD-treated ob/ob displayed a normal insulin response with 100 (71%) or 2000 (158%) microU/ml insulin. Additional studies were performed using ZDF rats treated with/without TZD for 7 days. In vivo 2-DOG glucose uptake into soleus, gastrocnemius, and diaphragm muscles was measured during euglycemic-hyperinsulinemic clamp. Compared with lean rats, muscle 2-DOG uptake in ZDF was reduced by 52% (soleus) or 71% (diaphragm). Partial (40-60%) normalization of the reduced 2-DOG uptake was evident in TZD-treated ZDF rats. In contrast to the effect of in vivo treatment on muscle insulin action, preincubation of isolated soleus muscles from naive lean or ob/ob mice for 5 h with 100 nM TZD did not affect insulin-stimulated 2-DOG uptake. We conclude: 1) PPARgamma is expressed in myocytes within skeletal and cardiac muscle. 2) In vivo activation of PPARgamma by treatment of insulin-resistant mice/rats with a potent TZD corrects impaired muscle insulin action. 3) The lack of a direct effect on muscle after 5 h in vitro TZD incubation suggests that changes in insulin action may require a longer duration of PPARgamma activation or that improved muscle insulin sensitivity may result from an indirect in vivo effect of PPARgamma activation (e.g. changes in systemic lipid metabolism).
Wegener's granulomatosis (WG) is a multisystem granulomatous, necrotizing vasculitis of presumed autoimmune origin that affects small- to medium-sized blood vessels. The respiratory tract and kidneys are typically involved (Gross and Reinhold-Keller, "Clinical features of primary ANCA-associated vasculitis" in Oxford textbook of rheumatology, third edition, 2004). The limited form usually involves the head and neck, lacks renal involvement, and may not progress to generalized disease (Cassan et al., Am. J. Med. 49:366-379, 1970). Ocular involvement, which may be the initial manifestation, is often encountered and can result in significant morbidity and possibly blindness (Pakrou et al., Semin. Arthritis Rheum. 35:284-292, 2006). We report an unusual case of WG presenting as an orbital mass. The diagnostic triad of granulomatous inflammation with multinucleated giant cells, vasculitis, and necrosis was discovered on histopathology (McDonald and Edwards, JAMA 173:1205-1209, 1960).
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