Increased serum amyloid a levels reflect colitis severity and precede amyloid formation in IL-2 knockout mice

The lack of sensitive and relatively non-invasive measures has hampered mon itoring the clinical course of spontaneously developing colitis in IL-2-def icient ((-/-)) mice. We selected (i) to study the correlation of the acute phase plasma proteins serum amyloid A (SAA) and serum amyloid P component ( SAP) levels with colonic disease and (ii) to characterize the amyloidosis i n the IL-2(-/-) animals. IL-2(-/-) mice exhibited increasing severity of gr oss intestinal inflammation with age, confined to the distal colon. Histolo gically, the colonic disease score increased serially in IL-2(-/-) animals. Wild-type mice showed no activity, while 16-week-old IL-2(-/-) animals had minimal colitis with small ulcers and lamina propria inflammatory infiltra te. Periportal hepatitis was present and positive Congo red staining indica ted amyloidosis of the liver and spleen in 16 week IL-2(-/-) mice. SAA immu nostaining in the liver and spleen was increased in the 8 week and 16 week IL-2(-/-) and 16 week IL-2(+/-) animals indicating AA amyloid deposits. Pla sma SAA and SAP levels were markedly elevated, and generally preceded the o nset of colitis and reflected its severity. Northern analysis showed marked ly increased SAA expression in the liver and intestine of IL-2(-/-) and int estine of IL-2(+/-) 16-week-old animals. Increased intestinal expression of SAA3 (lamina propria macrophages) indicates local inflammation in IL-2(+/- ) animals at 16 weeks. Treatment of 3-week-old animals with systemic IL-2 o r IL-1 receptor antagonist (IL-1ra) delayed inflammation, postponed the inc rease in SAA levels and minimized disease onset. These results further demo nstrate that IL-2 plays a significant role in normal immune responses in th e body and that plasma SAA levels both reflect colonic disease severity and may indicate subclinical disease in both IL-2(-/-) and IL-2(+/-) mice. Fur thermore. The mechanism of IL-2-deficient induced colitis appears to be med iated in part through the increase in IL-1. In addition, the IL-2(-/-) mous e of spontaneous enterocolitis may provide a unique system for studying spo ntaneously developing AA amyloidosis. (C) 2000 Academic Press.