Plasma IL-33 in atopic patients correlates with pro-inflammatory cytokines and changes cholesterol transport protein expression: a surprising neutral overall impact on atherogenicity.

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-γ, TNF-α, IL-17α, 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-γ (r = 0.85), TNFα (r = 0.9) and IL-17α (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-γ, TNF-α and IL-17α 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.

Immunotherapeutic strategies for the treatment of malignant melanoma.

The incidence of cutaneous malignant melanoma is increasing at a faster rate than any other cancer worldwide. Despite new advances in surgical management of melanoma, this malignancy remains one of the most aggressive and intractable to treat among other solid tumors. Continuous search for better therapeutics led to the development of various immunological approaches applicable to the treatment of this melanocytic malignancy. Multiple peptide, dendritic cell, adjuvant, lymphocyte, and virus-based strategies were established and tested in preclinical and clinical studies with varying degrees of clinical success. However, the most recent investigations in melanoma immunotherapy have clearly demonstrated that complex vaccines and the combination of different approaches, such as the use of dendritic cell vaccines in conjunction with costimulatory molecules, are superior to conventional immunization protocols in induction of tumor-specific immune responses. These recent studies open new perspectives for the development of efficient melanoma immunotherapeutics suitable for the treatment of primary and metastatic disease.