Objectives-Secretory phospholipase A 2 (sPLA 2 ) enzymes hydrolyze the sn-2 fatty acyl ester bond of phospholipids to produce a free fatty acid and a lysophospholid. Group V sPLA 2 is expressed in cultured macrophage cells and has high affinity for phosphatidyl choline-containing substrates. The present study assesses the presence of group V sPLA 2 in human and mouse atherosclerotic lesions and its activity toward low-density lipoprotein (LDL) particles. Methods and Results-Group V sPLA 2 was detected in human and mouse atherosclerotic lesions by immunohistochemical staining. Electron microscopic analysis showed that mouse group V sPLA 2 -modified LDL is significantly smaller (mean diameterϮSEMϭ25.3Ϯ0.25 nm) than native LDL (mean diameterϮSEMϭ27.7Ϯ0.29 nm). Hydrolysis by group V sPLA 2 induced spontaneous particle aggregation; the extent of aggregation was directly proportional to the degree of LDL hydrolysis. Group V sPLA 2 modification of LDL led to enhanced lipid accumulation in cultured mouse peritoneal macrophage cells. Conclusions-Group V sPLA 2 may play an important role in promoting atherosclerotic lesion development by modifying LDL particles in the arterial wall, thereby enhancing particle aggregation, retention, and macrophage uptake. Key Words: atherosclerosis Ⅲ group V secretory phospholipase A 2 Ⅲ LDL aggregation Ⅲ macrophages A critical event in early atherogenesis is the retention of low-density lipoprotein (LDL) particles in the subendothelium. Accumulating evidence points to LDL aggregation and LDL fusion as key elements of atherogenic lipid accumulation in the artery wall. 1 Aggregated lipoproteins that appear to be derived from LDL are prominent in early atherosclerotic lesions. 2,3 Aggregated LDL is taken-up by macrophages in vitro at an enhanced rate compared with non-aggregated LDL, leading to macrophage cholesterol accumulation and foam cell formation. 4,5 Because native LDL particles do not form aggregates, LDL modification appears to be a prerequisite for aggregation/fusion. Studies in vitro indicate that hydrolysis of LDL by secretory phospholipases A 2 (sPLA 2 ) may be linked to LDL aggregation and/or fusion and enhanced retention in the subendothelium. 3,6 The sPLA 2 family comprises a group of enzymes that hydrolyze the fatty acid esterified at the sn-2 position of glycerophospholipids. 7 The secreted enzymes are of low molecular weight (14 kDa), highly enriched in disulfide bonds, and require 1 to 10 mmol/L calcium for activity. The major secreted form present in synovial fluid, termed group IIa, has been proposed to act as a mediator of inflammatory responses. During acute or chronic inflammation, the concentration of group IIa sPLA 2 can increase by Ͼ100-fold in inflammatory fluids and plasma. 8,9 Immunohistochemistry studies have established that group IIa sPLA 2 is present in normal arterial tissue and increased in atherosclerotic lesions. 10 -12 We recently reported that macrophage expression of human group IIa sPLA 2 significantly enhances atherosclerotic lesion formation in...

In an effort to develop a molecular classification scheme for Crohn's disease (CD), mucosal biopsies from 69 CD patients and 28 normal controls were analyzed for expression of the RelA subunit of nuclear factor (NF)-kappaB, A20 (a negative regulator of NF-kappaB), polymeric immunoglobulin receptor (pIgR), tumor necrosis factor (TNF), and interleukin (IL)-8. Principal component analysis was used to classify individuals into three subsets based on patterns of biomarker expression. Set 1 included normal subjects and CD patients with mild disease and good responses to therapy, thus defining "normal" biomarker expression. CD patients in set 2, characterized by low expression of all five biomarkers, had moderate to severe disease and poor responses to immunosuppressive and anti-TNF therapy. Patients in set 3, characterized by low expression of RelA, A20, and pIgR, normal TNF and elevated IL-8, had acute inflammation that responded well to therapy. Classification of CD patients by these biomarkers may predict disease behavior and responses to therapy.

Background Gene-environment interplay modulates Inflammatory Bowel Diseases [IBD]. Dioxin-like compounds can activate the Aryl Hydrocarbon Receptor [AhR] and alter macrophage function as well as T cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Design DSS colitis was induced in C57BL/6 AhR null mice [AhR −/−], heterozygous mice [AhR−/+], and their wild type [WT] littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results AhR −/− mice died before the end of the treatment. However, AhR −/+ mice exhibited decreased disease activity compared to WT mice. The AhR −/+ mice expressed less proinflammatory cytokines such as TNFα (6.1 versus 15.7 fold increase) and IL17 (23.7 versus 67.9 fold increase) and increased antiinflammatory IL-10 (2.3 fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR −/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 – 19.9, and IL8-10 fold increase). Conclusion Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking or administration of AhR antagonists could be viable strategies for the treatment of IBD.

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