Expression of ASC in Renal Tissues of Familial Mediterranean Fever Patients with Amyloidosis: Postulating a Role for ASC in AA Type Amyloid Deposition BANU BALCI-PEYNIRCIOGLU,*, ANDREA L. WAITE, PHILIP SCHANER,à ZIHNI EKIM TASKIRAN,* NEIL RICHARDS, DICLEHAN ORHAN,§ SAFAK GUCER,§ SEZA OZEN,jj DEBORAH GUMUCIO, AND ENGIN YILMAZ* ,1 *Hacettepe University, Faculty of Medicine, Department of Medical Biology, Ankara, Turkey;  University of Michigan, Department of Cell and Developmental Biology, Ann Arbor, MI 48109-2200; àUniversity of Alabama at Birmingham, Division of Radiology/Oncology, Birmingham, AL 35294-3300; §Hacettepe University, Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Department of Child Health, Unit of Pediatric Pathology, Ankara, Turkey; and jj Hacettepe University, Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Department of Child Health, Nephrology and Rheumatology Unit, Ankara, Turkey Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis; in some cases, ensuing amyloidosis results in kidney damage. Treatment with colchi- cine reduces the frequency and severity of FMF attacks and prevents amyloidosis, although the mechanisms behind these effects are unknown. Pyrin, the protein product of the MEFV gene, interacts with ASC, a key molecule in apoptotic and inflammatory processes. ASC forms intracellular speck-like aggregates that presage cell death. Here we show that cell death after ASC speck formation is much slower in nonmyeloid cells than in myeloid cells. Additionally, we demonstrate that colchicine prevents speck formation and show that specks can survive in the extracellular space after cell death. Because we also found that ASC is expressed in renal glomeruli of patients with FMF but not in those of control patients, we posit that high local ASC expression may result in speck formation and that specks from dying cells may persist in the extracellular space where they have the potential (perhaps in association with pyrin) to nucleate amyloid. The fact that speck formation requires an intact microtubule network as shown here could potentially account for the ability of prophylactic colchicine to prevent or reverse amyloidosis in patients with FMF. Exp Biol Med 233:1324–1333, 2008 Key words: ASC; amyloidosis; speck; microtubules Introduction The hereditary autoinflammatory diseases, including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumor necrosis factor–associ- ated periodic syndrome (TRAPS), and hyper-IgD syndrome are associated with mutations in several proteins now believed to be involved in innate immune pathways (1). These diseases are characterized by systemic inflammation with high acute phase inflammatory markers and especially high levels of serum amyloid A (SAA). Secondary amyloidosis is a serious and life-threatening complication for patients with FMF, TRAPS, and CAPS (2). In the case of hyper-IgD syndrome, amyloidosis is much less common but has been reported (3). FMF is the most common of the autoinflammatory diseases and is characterized by recurrent attacks of fever with localized, painful inflammation. Attacks are often associated with high levels of acute phase reactants, and inflammation typically involves the peritoneum, pleura, joints, and skin (4). More than in any of the other periodic fever syndromes, FMF makes patients susceptible to multiorgan deposition of amyloid. In fact, before the use This work was supported by grant 06 D03101004 from Hacettepe University (E.Y.) and by the R01 grant AI053262 from the National Institutes of Health (D.L.G.). 1 To whom correspondence should be addressed at Hacettepe University, Tip Fakultesi, Tibbi Biyoloji AD, Rektorluk Binasi, A Kapisi, 4. Kat, 06100 Sihhiye, Ankara, Turkey. E-mail: eyilmaz@hacettepe.edu.tr Received March 24, 2008. Accepted July 7, 2008. 1324 DOI: 10.3181/0803-RM-106 1535-3702/08/23311-1324$15.00 Copyright Ó 2008 by the Society for Experimental Biology and Medicine at SAGE Publications on November 19, 2014 ebm.sagepub.com Downloaded from