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Cyclophilin C-Associated Protein: a Normal Secreted Glycoprotein That Down-Modulates Endotoxin and Proinflammatory Responses in Vivo

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Cyclophilin C-Associated Protein: a Normal Secreted Glycoprotein That Down-Modulates Endotoxin and Proinflammatory Responses in Vivo Proc. Natl. Acad. Sci. USA Vol. 96, pp. 3006–3011, March 1999 Immunology Cyclophilin C-associated protein: A normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo MEG TRAHEY*† AND IRVING L. WEISSMAN Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Irving L. Weissman, January 7, 1999 ABSTRACT Mouse cyclophilin C-associated protein (Cy- homo-multimer of several million daltons (12). Levels of CAP) is a member of the scavenger-receptor cysteine-rich do- hMac-2-BP are elevated in the serum of some patients with main superfamily and is 69% identical to the human Mac-2 breast and ovarian cancer (13) and in patients infected with binding protein. Here, we show that CyCAP is a widely expressed HIV as they progress to AIDS (14), suggesting that hMac-2-BP secreted glycoprotein that modulates the host response to endo- may be involved in the host response to tumors and infections toxin. Gene-targeted CyCAP-deficient mice are more sensitive to (8). Ectopic expression of hMac-2-BP in two tumor cell lines the lethal effects of endotoxin. In response to endotoxin, CyCAP- suppresses their growth in nude mice (15). In vitro, purified deficient mice overproduced interleukin 12 and interferon-g hMac-2-BP stimulates natural-killer and lymphokine- systemically and tumor necrosis factor a locally; these are activated-killer activity of human peripheral blood lympho- proinflammatory molecules that also promote T helper 1 re- cytes (8) and induces production of interleukin (IL)-1 and IL-6 sponses. Furthermore, macrophages stimulated in vitro with by human blood monocytes (16). CyCAP expression in mac- endotoxin in serum deficient in CyCAP secreted more tumor rophages can be up-regulated by adherence and by the inflam- necrosis factor a, supporting the proposal that CyCAP specifi- matory cytokines tumor necrosis factor a (TNF-a) and inter- cally down-modulates endotoxin signaling. feron-g (IFN-g; ref. 2). These studies are consistent with a role for CyCAPyhMac-2-BP in immune regulation and inflamma- Murine cyclophilin C-associated protein (CyCAP) was iden- tion. Additionally, hMac-2-BP binds to immobilized endotoxin y tified on the basis of its ability to bind the peptidylprolyl receptor CD14 in a serum-dependent and endotoxin isomerase cyclophilin C (cypC). This interaction was shown in lipopolysaccharide (LPS)-dependent fashion (17), and the y cellular extracts and was inhibited by the immunosuppressive hMac-2-BP ligand, Mac-2 galectin-3, can bind LPS in vitro y drug cyclosporin A (CsA; ref. 1). CyCAP was identified (18). These data are consistent with a role for CyCAP hMac- independently as a cell-surface-associated antigen on mouse 2-BP in the inflammatory response, likely through interactions macrophages and was named MAMA (2). with CD14 and LPS. To investigate this possibility, we have CyCAP is a member of the scavenger-receptor cysteine-rich characterized the biochemical nature and expression of Cy- (SRCR) domain superfamily (2, 3), a family defined by a CAP and investigated the role of CyCAP in the host response 2y2 cysteine-rich domain first identified in the class A type I to endotoxin by using CyCAP mice. scavenger receptor (SR-AI; ref. 4). This evolutionarily con- served domain is found in diverse transmembrane and secreted MATERIALS AND METHODS glycoproteins, including CD5, CD6, M130, complement factor 1, WC1 antigen, and the speract receptor (5). Many of these Mice. Mice were maintained in the animal facility of the Stanford Medical School Veterinary Service Center. proteins are expressed by immune cells (e.g., B cells, T cells, 3 and macrophages) that are implicated in host defense and (C57BL CBA)F1 mice were obtained from The Jackson immune regulation. It is likely that SRCR domains are in- Laboratory. volved in mediating specific protein–protein interactions (5), Cell Culture. MM55 mouse kidney cells (ATCC CRL 6436) although this has been established clearly for only one family and the HT-29 human colon carcinoma cell line (ATCC HTB 38) were grown in DMEM with 10% fetal calf serum, 2 mM member, CD6. The SRCR domain of CD6 mediates binding to y the activated leukocyte cell adhesion molecule (6). glutamine, and penicillin streptomycin. Peritoneal exudate Among SRCR domain family members, CyCAP is most cells (PECs) were collected from peritoneal lavages of un- closely related to the human Mac-2 binding protein (hMac-2- stimulated mice or mice 3 days after i.p. injection with 4% BP; also known as L3 antigen; ref. 7), the melanoma-associated thioglycolate broth. Bone-marrow-derived macrophages were antigen (7), and the 90K tumor-associated antigen (8). Based obtained by differentiation of nonadherent bone-marrow cells on sequence similarity, it has been proposed that CyCAP is the in DMEM with 10% L cell conditioned medium (as a source mouse homologue of hMac-2-BP (2, 5). Although the se- of macrophage colony-stimulating factor). quence similarity is striking (69% identity at the protein level), Metabolic Labeling and Immunoprecipitation. For pulse– it was not known whether these two proteins are functionally chase labeling, MM55 cells were starved for cysteine and homologous or whether more closely related proteins exist. methionine for 20 min, pulsed for 10 min with 0.5 mCi of Indeed, CyCAP was identified first in cell extracts (1), and MAMA was proposed to be a membrane protein (2), whereas Abbreviations: CsA, cyclosporin A; CyCAP, cyclophilin C-associated hMac-2-BP is a secreted glycoprotein (7–11). protein; cypC, cyclophilin C; gbw, gram body weight; GST, glutathione S-transferase; hMac-2-BP, human Mac-2 binding protein; IFN-g, hMac-2-BP is expressed in many tissues, is found in serum, interferon-g; IL, interleukin; LPS, lipopolysaccharide; PEC, perito- breast milk, saliva, and urine (8, 12), and may function as a neal exudate cell; SR-AI, scavenger receptor class A type I; SRCR, scavenger-receptor cysteine-rich; TNF, tumor necrosis factor; Th, T The publication costs of this article were defrayed in part by page charge helper. *Present address: Montana Biotechnology Center, University of Mon- payment. This article must therefore be hereby marked ‘‘advertisement’’ in tana, Missoula, MT 59812. accordance with 18 U.S.C. §1734 solely to indicate this fact. †To whom reprint requests should be addressed. e-mail: traheym@ PNAS is available online at www.pnas.org. selway.umt.edu. 3006 Downloaded by guest on September 26, 2021 Immunology: Trahey and Weissman Proc. Natl. Acad. Sci. USA 96 (1999) 3007 L-[35S]methionine and L-[35S]cysteine (1,000–1,300 Ciymmol; Measuring Cytokine Levels After LPS Treatment. Wild- Amersham Pharmacia) in cysteine- and methionine-free type and CyCAP-deficient mice (E14-159 line; 8- to 9-week- DMEM with 5% dialyzed fetal calf serum, and chased in old females) were injected i.p. with 10 mgygbw LPS. Concen- medium with a 5-fold excess of cold methionine and cysteine. trations of IL-12 p70 and IFN-g in serum and concentrations For steady-state labeling, cells were incubated with 200–300 of TNF-a in peritoneal lavages were determined by ELISA mCiyml L-[35S]methionine and L-[35S]cysteine for 7–16 h. (Genzyme). Statistical analyses on cytokine release was done Supernatants were collected, and cells were lysed with 50 mM by using a two-tailed t test. Tris, pH 7.5y150 mM NaCly0.5% Triton X-100y1 mM phe- TNF-a Release by PECs in Vitro. PECs were obtained from nylmethylsulfonyl fluoride. Cell lysates and media were pre- 8- to 12-week-old unstimulated CyCAP 2y2 mice, pooled, cleared with anti-Rat IgG protein A Sepharose (Sigma). and cultured in Iscove’s serum-free medium containing LPS CyCAP was immunoprecipitated with a rat polyclonal serum and 5% serum from CyCAP 2y2 or 1y1 mice for 6 h. TNF-a against CyCAP purified from MM55 mouse kidney cell su- levels in the media were determined by ELISA. The mouse pernatants. Macrophage antigens Mac-1 and Mac-2 were sera used for culturing were age- and sex-matched and negative immunoprecipitated with monoclonal antibodies M1y70 (19) for TNF-a, as determined by ELISA. In an independent and M3y38 (20), respectively. Immune complexes were col- experiment, peritoneal lavages of individual mice were kept lected on anti-Rat IgG protein A Sepharose. separate and treated as above, except that the cell concentra- cypC-GST-Glutathione Agarose Precipitation of CyCAP. tion varied with each animal from 1 3 106 cells to 5 3 106 cells CyCAP was affinity-isolated with cypC-glutathione S- per ml and that one dose of 0.1 mgyml LPS was used for transferase (GST) fusion protein and glutathione agarose as stimulation. Statistical analysis on TNF-a release from indi- previously described (1). CyCAP can bind to cypC only in the vidual mice was performed by using a paired t test. absence of CsA (1). Statistical Analyses. P values were calculated with the Northern and Southern Hybridization. Hybridizations were STATVIEW (Abacus Concepts, Berkeley, CA) and EXCEL (Mi- performed as described (21). Total RNA from mouse kidney crosoft) programs. and liver was prepared by the LiClyurea method (22) and resolved on 1% formaldehydeyagarose gels and transferred to Genescreen (NEN). Filters were hybridized with [a-32P]dCTP- RESULTS labeled CyCAP and cypA cDNA probes prepared by random CyCAP Is the Mouse Homologue of hMac-2-BP. The issue priming (Ready To Go, Amersham Pharmacia). For low- of whether CyCAP is the mouse homologue of hMac-2-BP was stringency Southern hybridization, filters were hybridized with addressed by Southern blot analysis of mouse genomic DNA 32 3 P-labeled probes in 5 standard saline citrate (0.15 M with CyCAP and hMac-2-BP probes at low stringency.
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