Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations.

Familial Mediterranean fever (FMF) is a recessive inherited autoinflammatory syndrome. Patients with FMF have symptoms such as recurrent fever and abdominal pain, sometimes accompanied by arthralgia. Biopsy specimens have revealed substantial neutrophil infiltration into synovia. FMF patients have a mutation in the Mediterranean fever gene, encoding pyrin, which is known to regulate the inflammasome, a platform for processing interleukin (IL)-1ß. FMF patients heterozygous for E148Q mutation, heterozygous for M694I mutation, or combined heterozygous for E148Q and M694I mutations, which were found to be major mutations in an FMF study group in Japan, suffer from arthritis, the severity of which is likely to be lower than in FMF patients with M694V mutations. Expression plasmids of wild-type (WT) pyrin and mutated pyrin, such as E148Q, M694I, M694V, and E148Q+M694I, were constructed, and SW982 synovial sarcoma cells were transfected with these expression plasmids. IL-8 and IL-6 were spontaneously secreted from the culture supernatant of SW982 cells without any stimulation, whereas IL-1ß and TNF-α could not be detected even when stimulated with lipopolysaccharide. Notably, two inflammasome components, ASC and caspase-1, could not be detected in SW982 cells by Western blotting. IL-8 but not IL-6 secretion from SW982 cells was largely suppressed by WT pyrin, but less suppressed by mutated pyrin, which appeared to become weaker in the order of E148Q, M694I, E148Q+M694I, and M694V mutations. As for IL-8 and IL-6, similar results were obtained using stable THP-1 cells expressing the WT pyrin or mutated pyrins, such as M694V or E148Q, when stimulated by LPS. In addition, IL-8 secretion from mononuclear cells of FMF patients was significantly higher than that of healthy volunteers when incubated on a culture plate. Thus, our results suggest that IL-8 secretion from SW982 synovial sarcoma cells suppressed by pyrin independently of inflammasome is affected by pyrin mutations, which may reflect the activity in FMF arthritis.

Microvasculature of carotid atheromatous plaques: hemorrhagic plaques have dense microvessels with fenestrations to the arterial lumen.

BACKGROUND: Microvessels in atheromatous plaques are well known to play a role in plaque vulnerability associated with intraplaque hemorrhage, but their architecture remains unclear. The morphometry of the microvasculature and hemorrhage of human carotid atheromatous plaques (CAPs) were evaluated, and 3-dimensional (3D) reconstruction of the microvessels was performed. METHODS: CAPs were obtained by endarterectomy in 42 patients. The specimens were analyzed using light microscopy. Plaque hemorrhage was defined as an area-containing red blood cells (>1 mm2). To determine the histopathologic features of plaque hemorrhage, the plaque area was divided into 4 regions: cap, shoulder, lipid/necrotic core, and media. Then, the density of microvessels and macrophages in each region was quantified. Two representative lesions with either hemorrhagic or nonhemorrhagic plaque were cut into 90 serial sections. The sections were double stained with anti-CD34 and anti-α smooth muscle actin antibodies, scanned using a digital microscope, and reconstructed using TRI-SRF2 software. RESULTS: The hemorrhagic plaques showed a higher density of microvessels than nonhemorrhagic plaques in the shoulder, cap, and lipid/necrotic core (P=.03, .009, and .001, respectively), and there was positive correlations between its density and macrophages in each regions (P<.001, .001, and .019, respectively). 3D imaging also revealed dense microvessels with a network structure in the cap and shoulder regions of hemorrhagic plaques, and some of the vessels were fenestrated to the arterial lumen. CONCLUSIONS: The microvasculature of plaques with intraplaque hemorrhage was dense, some of which fenestrated to the arterial lumen. The pathologic 3D imaging revealed precise architecture of microvasculature of plaques.

[The inflammasome].

Inflammation is a protective response intended to eliminate primary causes of tissue injury, leading to tissue repair and adaptation in a focal lesion. It is thought that various factors are involved in the histopathological responses to tissue injury. One of the inflammatory cytokines, interleukin(IL)-1beta, is thought to play an important role in inflammatory responses. The inflammasome is a multi-protein complex, required for IL-1beta processing and activation to induce inflammation. Over the past decade, evidence has accumulated that the inflammasome contributes significantly to the pathogenesis of various diseases. In this review, we discuss the function of inflammasome and inflammasome-related diseases, that are now expanding beyond inflammation.

Primary cardiac rhabdomyosarcoma developed after receiving radiotherapy for left breast cancer 18 years prior.

The heart is an organ where primary malignant tumors rarely develop. In particular, the incidence of cardiac rhabdomyosarcoma (RMS) is extremely low. It has been reported that the risk of second malignant tumors in mediastinum is increased by radiotherapy in women with breast cancer. However, little is known about the association between irradiation to heart and cardiac RMS. Here, we report a case of a 68-year-old woman with primary cardiac RMS. She suddenly presented syncope at a workplace, and was taken to the emergency room at our hospital. Several imaging tests, including echocardiogram and cine magnetic resonance imaging, detected two tumors in the right ventricle (RV) and its outflow tract, which had almost obstructed the main trunk of the pulmonary artery (PA). To avoid sudden PA occlusion by the tumor, we emergently performed surgical excision of the tumors from the RV. Pathological analysis revealed that these tumors were embryonal type RMS. She had received radiotherapy after mastectomy for left breast cancer 18 years previously, and no recurrence of breast cancer had been detected. This cardiac RMS is considered as a second malignant tumor related to radiotherapy for breast cancer. .