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Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132
There is increasing epidemiologic evidence implying a role for chronic infection in atherosclerosis and that microbial TLR agonists may contribute to this disease. Mycoplasma arthritidis is an agent of acute and chronic inflammatory disease in rodents, and has been used extensively as a model for defining the mechanisms involved in arthritis and other inflammatory diseases. We have purified a 28-kDa, apolipoprotein A-1 (apoA-1)-like TLR2-dependent macrophage-activating moiety from a culture of a virulent strain of M. arthritidis. ApoA-1 similarly isolated from uninoculated mycoplasma medium was without bioactivity. The activity of the mycoplasma-derived molecule was resistant to heat and to digestion with proteinase K, but was susceptible to alkaline hydrolysis and H2O2 oxidation. Infrared profiles of normal apoA-1 and that derived from mycoplasma were distinct. Unlike the activity of other mycoplasmal TLR2 agonists such as macrophage-activating lipopeptide-2, activity of the M. arthritidis-derived 28-kDa component was dependent upon CD14, a coreceptor for LPS. Finally, we showed that bioactive lipopeptides prepared from M. arthritidis grown in serum-free medium and also from a 41-kDa known bioactive lipoprotein of M. arthritidis, avidly bound to purified apoA-1 that separated out by SDS-PAGE, induced TNF-
and IL-12p40 both in vitro and in vivo. ApoA-1 is a key functional component of the high-density lipoprotein cholesterol complex by scavenging and removing unwanted lipids. Our finding that this molecule can acquire macrophage-activating properties from microbial TLR2-dependent agonists suggests a novel mechanism whereby some microbial agents might reverse the protective role of apoA-1, thus contributing to the genesis of atherosclerosis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Nora Eccles Treadwell Foundation and by Grant AR 02255 from the National Institute of Arthritis and Metabolic Diseases. B.C.C. is the holder of the Nora Eccles Harrison Presidential Endowed Chair in Rheumatology.
2 Address correspondence and reprint requests to Dr. Barry C. Cole, Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132. E-mail address: Barry.Cole{at}hsc.utah.edu
3 Abbreviations used in this paper: HDL, high-density lipoprotein; apoA-1, apolipoprotein A-1; HS apoA-1, horse serum-derived apoA-1; IR, infrared; KO, knockout; LDL, low-density lipoprotein; MALP-2, macrophage-activating lipopeptide-2; MAM, M. arthritidis mitogen; Mm apoA-1, mycoplasma-modified apoA-1; NS, normal saline; OG, n-octyl-
-glucopyranoside; OGex, OG extract; Pam3CSK4, Pam3-Cys-Ser-(Lys)4 3HCl; PK, proteinase K; SAg, superantigen.
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