Paracrine IL-33 Stimulation Enhances Lipopolysaccharide-Mediated Macrophage Activation

BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation

Evidence For The Control Of Aggrecanases By Insulin And Glucose In Alzheimer'S Disease

Objective: Alzheimer's disease (AD) is a progressive and irreversible central nervous system disease, which slowly destroys cognitive skills and memory, and eventually even the ability to handle the simplest tasks. The initiation and progression of AD is a poorly understood complex process. Here, we have investigated possible biological mechanisms that could be responsible for the increased risk for diminished brain function associated with diabetes in AD. Method: The U87 cell line (human primary glioblastoma cell line) was cultured in Dulbecco's modified Eagle's medium. Cells were incubated with insulin (10 mu g/ml), low glucose (11 mM, 2 mg/ml) and high glucose (55 mM, 10 mg/ml) for 48 hours. Cells were harvested and protein isolations were performed. Primary anti-ADAMTS5, anti-IL-33, anti-NF kappa B, and anti-GAPDH antibodies were used to detect corresponding proteins and to measure band densities in Western membranes using a specific program. Results: Western blot analysis showed ADAMTS5 protein decreases in insulin-applied U87 cells. High glucose application led to a notable increase in ADAMTS5 levels in cells, while low glucose application caused a moderate increase in ADAMTS5 levels. An apparent induction of IL-33 protein was observed in high glucose-applied cells, while a moderate decrease was noted in the low-glucose applied group. Insulin administration led to a decrease in IL-33 levels. Immunoreaction of NF kappa B with corresponding antibody was found to be sharply decreased in insulin-applied cells while low and high glucose application led to a moderate decrease in NF kappa B. Conclusion: This is the first reported study that has investigated both aggrecanases and inflammation mediators in the same experimental setup with U87 cells and interpreted the results in the various aspects of AD pathophysiology related to diabetes and hyperglycemia. Our findings suggest that insulin and glucose may have important functions in the synthesis of ADAMTS, IL-33, and NF kappa B through undefined mechanism(s). Further investigations dealing with all aggrecanases and other class of ADAMTS enzymes should be carried out together with the above-mentioned parameters with the collaboration of molecular biology, genetics, immunology, and other related disciplines in order to elaborate the pathophysiological importance of ADAMTS enzymes and inflammation mediators in AD.WoSScopu

Disease-associated functions of IL-33: the new kid in the IL-1 family

Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis. The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (T<sub>H</sub>2) cells and mast cells. IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting T<sub>H</sub>2-type immune responses. However, IL-33 can also promote the pathogenesis of asthma by expanding T<sub>H</sub>2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. Thus IL-33 could be a new target for therapeutic intervention across a range of diseases