Faculty Bibliography

BACKGROUND: Leptin, an adipocyte-derived circulating cytokine that signals nutritional status, may play a role in the development of psoriasis and its associated systemic diseases. Patients with psoriasis have significantly decreased serum leptin levels compared with controls. AIM: To investigate the effect of two commonly used anti-psoriatic biologic drugs, adalimumab and ustekinumab, on leptin and leptin receptor expression in human macrophages. METHODS: THP-1 differentiated macrophages were cultured under the following conditions: (i) untreated control, (ii) adalimumab 5 mug/mL, (iii) ustekinumab 1 mug/mL and (iv) ustekinumab 5 mug/mL. Expression of leptin and leptin receptors were measured using real-time quantitative PCR and immunoblotting techniques. RESULTS: The presence of either adalimumab or ustekinumab in growth medium significantly upregulated expression of leptin receptor in THP-1 human macrophages to 1.98 +/- 0.47 and 2.09 +/- 0.24, respectively (n = 3, P < 0.01) vs. 1.12 +/- 0.19 for untreated control cells. However, only ustekinumab at a concentration of 5 mug/mL augmented expression of leptin to 1.99 +/- 0.56 (n = 3, P < 0.01) vs. control untreated cells. CONCLUSIONS: Enhanced leptin and leptin receptor expression in macrophages exposed to therapeutic levels of ustekinumab suggest a novel immunomodulatory mechanism for this biologic drug. Further mechanistic studies may yield targeted treatment using the leptin pathway, which could reduce the common obesity-related complications of psoriasis while alleviating symptoms and improving prognosis.

Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Numerous investigations by our group and others have indicated cardioprotective and anti-inflammatory properties of resveratrol. The present study explored potential atheroprotective actions of resveratrol on cholesterol efflux in cultured human macrophages exposed to plasma from systemic lupus erythematosus (SLE) patients. These results were confirmed in ApoE(-/-)Fas(-/-) double knockout mice, displaying a lupus profile with accelerated atherosclerosis. Resveratrol treatment attenuated atherosclerosis in these mice. THP-1 human macrophages were exposed to 10% pooled or individual plasma from patients who met diagnostic criteria for SLE. Expression of multiple proteins involved in reverse cholesterol transport (ABCA1, ABCG1, SR-B1, and cytochrome P450 27-hydroxylase) was assessed using QRT-PCR and Western blotting techniques. Ten-week-old ApoE(-/-)Fas(-/-) double knockout mice (n = 30) were randomly divided into two equal groups of 15, one of which received 0.01% resveratrol for 10 consecutive weeks. Atherosclerosis progression was evaluated in murine aortas. Bone marrow-derived macrophages (BMDM) were cultured and expression of cholesterol efflux proteins was analyzed in each group of mice. Our data indicate that inhibition of cholesterol efflux by lupus plasma in THP-1 human macrophages is rescued by resveratrol. Similarly, administration of resveratrol in a lupus-like murine model reduces plaque formation in vivo and augments cholesterol efflux in BMDM. This study presents evidence for a beneficial role of resveratrol in atherosclerosis in the specific setting of SLE. Therefore, resveratrol may merit investigation as an additional resource available to reduce lipid deposition and atherosclerosis in humans, especially in such vulnerable populations as lupus patients.

BACKGROUND:Diffuse alveolar hemorrhage (DAH) is an uncommon but potentially life-threatening manifestation of systemic lupus erythematosus (SLE) associated with high mortality. Although survival and its associated clinical, laboratory, and therapeutic features have been reported for case reports and series, they have not been systematically reviewed. OBJECTIVES/OBJECTIVE:The purpose of this systematic review was to assess survival of episodes of DAH in SLE over 3 decades and to categorize trends in therapies, commonly utilized to treat this disorder. RESULTS:Overall, SLE patients survived 61% of 174 DAH episodes representing 140 patients. Episode survival was 67% in the time period from 2000 to 2013. Corticosteroids were nearly universally used therapeutically, and cyclophosphamide was used in 55%. Plasmapheresis was used in 31% and did not appear to be associated with survival. CONCLUSIONS:Diffuse alveolar hemorrhage in SLE still carries a high risk of mortality; however, survival trends appear to demonstrate an increase from approximately 25% in the 1980s to 67% in the current decade. Increased use of cyclophosphamide appears to be associated with better survival, whereas plasmapheresis does not appear to influence outcome. Although these results need to be interpreted with caution because they are not derived from randomized controlled trials, we believe this represents the largest reported compilation of survival data in DAH associated with SLE.

OBJECTIVE: Interleukin (IL)-33 has been associated with atopic and inflammatory conditions. IL-33 may be atheroprotective inducing a Th1-to-Th2 immunologic switch. However, the role of IL-33 in cardiovascular disease remains unclear. This study examines the effect of physiological and elevated IL-33 levels in plasma from atopic patients (AP) on cholesterol metabolism in human macrophages as compared to plasma from healthy controls (HC). METHODS: Twenty-five AP and 25 HC were enrolled in this study. Plasma samples were analysed for levels of IL-33, IFN-gamma, TNF-alpha, IL-17alpha, IL-5 and soluble ST2. THP-1 differentiated macrophages were exposed to HC and AP plasma. Expression of proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), was measured using QRT-PCR and immunoblotting techniques. RESULTS: IL-33 was significantly higher in AP plasma: 106.7 +/- 95 pg/mL versus HC plasma (53.4 +/- 23 pg/mL). IL-33 concentration strongly correlated with levels of IFN-gamma (r = 0.85), TNFalpha (r = 0.9) and IL-17alpha (r = 0.94). No significant difference was found in soluble ST2 levels. An important contrast was observed for 27-hydroxylase: normal IL-33 in AP plasma amplified 27-hydroxylase while increased IL-33 suppressed it. Expression of CD36 and SR-A1 was greater in macrophages exposed to plasma with high IL-33, while CXCL16 was higher in cells grown in the presence of plasma with normal IL-33. CONCLUSIONS: Here, we demonstrate that high levels of IL-33 and a high IL-33/soluble ST2 ratio correlates with elevated levels of IFN-gamma, TNF-alpha and IL-17alpha as well as IL-5, demonstrating that IL-33 has pleiotropic effects. However, elevated IL-33 did not significantly impact lipid accumulation in macrophages overall. Given the wide variety of cellular responses regulated by IL-33, further investigation with a larger sample size will allow us to clarify the threshold concentration of IL-33 that leads to optimal cholesterol balance.

Primary Sjögren's syndrome can have multiple extra-glandular manifestations ranging from mild to severe. Treatment for extra-glandular manifestations is organ specific and therapies are targeted based on the primary organs involved. Preferred treatment options used for extra-glandular manifestations of Sjögren's syndrome are usually extrapolated from the physician's experience in treating similar manifestations in other autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematous. The lack of immunomodulating disease modifying drugs in Sjögren's syndrome can be frustrating for patients dealing with extra-glandular manifestations, however recent advances in the field has made the future look promising for new therapeutic options.