, 2009). The avid binding of SAP to DNA (Pepys and Butler, 1987) and chromatin (Butler et al., 1990) strongly suggests that SAP may play a role

in the appropriate, safe handling of these materials in vivo. More controversially it has been reported that SAP has an anti‐fibrotic effect, for which several different mechanisms have been claimed, most recently via stimulation of IL‐10 production ( Castaño et al., 2009). There is even more wide ranging controversy over possible biological SCH727965 concentration roles of human CRP, which has been claimed to be pro‐inflammatory, cytokine stimulating, pro‐atherogenic and pro‐thrombotic ( Ballou and Lozanski, 1992, de Maat and Trion, 2004, Labarrere and Zaloga, 2004, Bisoendial et al., 2005, Bisoendial et al., 2007a, Bisoendial

et al., 2007b and Bisoendial et al., 2009). However human SAP is a constitutive plasma protein with a circulating concentration in the range of about 20-50 mg/L ( Nelson et al., 1991) which is tightly regulated and almost constant in each individual. In contrast, human CRP is the classical, highly dynamic, rapidly responsive, BEZ235 solubility dmso entirely non‐specific acute phase protein with a 10,000 fold concentration range of about 0.05 to over 500 mg/L ( Shine et al., 1981 and Pepys and Hirschfield, 2003). Neither of these behaviors is consistent with a role in regulation of cytokine production and there is absolutely no clinical evidence in humans or experimental evidence in animals that endogenously produced high human CRP concentrations are inherently pro‐inflammatory. There are also compelling, well controlled, rigorous in vitro and in vivo studies which show no stimulation of cytokine production by the pentraxins ( Hirschfield et al., 2003, Hirschfield et al., 2005, Gillmore et al., 2004, Pepys, 2005, Pepys et al., 2005, Taylor et al., 2005, Taylor and van den Berg, 2007 and Tennent et al., 2008). Most reports on pro‐inflammatory effects of human CRP preparations have used inadequately characterized material isolated from human biological fluids or, more recently, commercial recombinant CRP produced in E. coli. The latter, manufactured only by the Oriental Yeast Company of Japan ( Tanaka

et al., 2002), is intended for use Sclareol as an immunochemistry standard, and is sold by many different biochemical reagent companies. It is heavily contaminated with endotoxin and likely other bacterial products ( Pepys et al., 2005). Although it has been claimed that a single gel filtration step removed all such contamination from this recombinant product ( Bisoendial et al., 2005), experiments in two independent laboratories, using authentic, highly purified, very low endotoxin content, human CRP did not produce any pro‐inflammatory effects in vitro or in vivo in mice ( Pepys et al., 2005 and Taylor et al., 2005). The reports claiming anti‐fibrotic activity of SAP are also poorly controlled and/or otherwise flawed ( Pilling et al., 2003, Haudek et al., 2006, Pepys et al.