Hepatocytes: a key cell type for innate immunity

Gao B, Jeong WI, Tian Z . Liver: an organ with predominant innate immunity. Hepatology 2008; 47: 729–736.

Rincon M . Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol 2012; 33: 571–577.

Calabrese LH, Rose-John S . IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol 2014; 10: 720–727.

Norris CA, He M, Kang LI, Ding MQ, Radder JE, Haynes MM et al. Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS One 2014; 9: e96053.

Dinarello CA . Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 2009; 27: 519–550.

Eder C . Mechanisms of interleukin-1beta release. Immunobiology 2009; 214: 543–553.

Bode JG, Albrecht U, Haussinger D, Heinrich PC, Schaper F . Hepatic acute phase proteins--regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-kappaB-dependent signaling. Eu J Cell Biol 2012; 91: 496–505.

Holers VM . Complement and its receptors: new insights into human disease. Annu Rev Immunol 2014; 32: 433–459.

Sarma JV, Ward PA . The complement system. Cell Tissue Res 2011; 343: 227–235.

Qin X, Gao B . The complement system in liver diseases. Cell Mol Immunol 2006; 3: 333–340.

Alper CA, Johnson AM, Birtch AG, Moore FD . Human C'3: evidence for the liver as the primary site of synthesis. Science 1969; 163: 286–288.

Volanakis JE . Transcriptional regulation of complement genes. Annu Rev Immunol 1995; 13: 277–305.

Morgan BP, Gasque P . Extrahepatic complement biosynthesis: where, when and why? Clin Exp Immunol 1997; 107: 1–7.

Morris KM, Aden DP, Knowles BB, Colten HR . Complement biosynthesis by the human hepatoma-derived cell line HepG2. J Clin Invest 1982; 70: 906–913.

Alper CA, Johnson AM, Birtch AG, Moore FD . Human C'3: evidence for the liver as the primary site of synthesis. Science 1969; 163: 286–288.

Bouwman LH, Roos A, Terpstra OT, de Knijff P, van Hoek B, Verspaget HW et al. Mannose binding lectin gene polymorphisms confer a major risk for severe infections after liver transplantation. Gastroenterology 2005; 129: 408–414.

Schwaeble W, Dahl MR, Thiel S, Stover C, Jensenius JC . The mannan-binding lectin-associated serine proteases (MASPs) and MAp19: four components of the lectin pathway activation complex encoded by two genes. Immunobiology 2002; 205: 455–466.

Stover CM, Lynch NJ, Hanson SJ, Windbichler M, Gregory SG, Schwaeble WJ . Organization of the MASP2 locus and its expression profile in mouse and rat. Mamm Genome 2004; 15: 887–900.

Pepys MB, Hirschfield GM . C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805–1812.

Mortensen RF . C-reactive protein, inflammation, and innate immunity. Immunol Res 2001; 24: 163–176.

Black S, Kushner I, Samols D . C-reactive protein. J Biol Chem 2004; 279: 48487–48490.

Inatsu A, Kinoshita M, Nakashima H, Shimizu J, Saitoh D, Tamai S et al. Novel mechanism of C-reactive protein for enhancing mouse liver innate immunity. Hepatology 2009; 49: 2044–2054.

Michelena J, Altamirano J, Abraldes JG, Affo S, Morales-Ibanez O, Sancho-Bru P et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology 2015; 62: 762–772.

Eklund KK, Niemi K, Kovanen PT . Immune functions of serum amyloid A. Crit Rev Immunol 2012; 32: 335–348.

Jensen LE, Whitehead AS . Regulation of serum amyloid A protein expression during the acute-phase response. Biochem J 1998; 334: 489–503.

Shah C, Hari-Dass R, Raynes JG . Serum amyloid A is an innate immune opsonin for Gram-negative bacteria. Blood 2006; 108: 1751–1757.

Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Muller M et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med 2010; 207: 1453–1464.

Lee HY, Kim MK, Park KS, Shin EH, Jo SH, Kim SD et al. Serum amyloid A induces contrary immune responses via formyl peptide receptor-like 1 in human monocytes. Mol Pharmacol 2006; 70: 241–248.

He R, Sang H, Ye RD . Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. Blood 2003; 101: 1572–1581.

He RL, Zhou J, Hanson CZ, Chen J, Cheng N, Ye RD . Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. Blood 2009; 113: 429–437.

Ather JL, Ckless K, Martin R, Foley KL, Suratt BT, Boyson JE et al. Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice. J Immunol 2011; 187: 64–73.

Lee HY, Kim SD, Shim JW, Lee SY, Lee H, Cho KH et al. Serum amyloid A induces CCL2 production via formyl peptide receptor-like 1-mediated signaling in human monocytes. J Immunol 2008; 181: 4332–4339.

Sandri S, Hatanaka E, Franco AG, Pedrosa AM, Monteiro HP, Campa A . Serum amyloid A induces CCL20 secretion in mononuclear cells through MAPK (p38 and ERK1/2) signaling pathways. Immunol Lett 2008; 121: 22–26.

Yuste J, Botto M, Bottoms SE, Brown JS . Serum amyloid P aids complement-mediated immunity to Streptococcus pneumoniae. PLoS Pathog 2007; 3: 1208–1219.

Ochrietor JD, Harrison KA, Zahedi K, Mortensen RF . Role of STAT3 and C/EBP in cytokine-dependent expression of the mouse serum amyloid P-component (SAP) and C-reactive protein (CRP) genes. Cytokine 2000; 12: 888–899.

Ma YJ, Doni A, Skjoedt MO, Honore C, Arendrup M, Mantovani A et al. Heterocomplexes of mannose-binding lectin and the pentraxins PTX3 or serum amyloid P component trigger cross-activation of the complement system. J Biol Chem 2011; 286: 3405–3417.

Mold C, Gresham HD, Du Clos TW . Serum amyloid P component and C-reactive protein mediate phagocytosis through murine Fc gamma Rs. J Immunol 2001; 166: 1200–1205.

Bharadwaj D, Mold C, Markham E, Du Clos TW . Serum amyloid P component binds to Fc gamma receptors and opsonizes particles for phagocytosis. J Immunol 2001; 166: 6735–6741.

Mold C, Baca R, Du Clos TW . Serum amyloid P component and C-reactive protein opsonize apoptotic cells for phagocytosis through Fcgamma receptors. J Autoimmun 2002; 19: 147–154.

Bijl M, Horst G, Bijzet J, Bootsma H, Limburg PC, Kallenberg CG . Serum amyloid P component binds to late apoptotic cells and mediates their uptake by monocyte-derived macrophages. Arthritis Rheum 2003; 48: 248–254.

Bickerstaff MC, Botto M, Hutchinson WL, Herbert J, Tennent GA, Bybee A et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 1999; 5: 694–697.

Kaur S, Singh PP . Serum amyloid P-component-mediated inhibition of the uptake of Mycobacterium tuberculosis by macrophages, in vitro. Scand J Immunol 2004; 59: 425–431.

Singh PP, Kaur S . Serum amyloid P-component in murine tuberculosis: induction kinetics and intramacrophage Mycobacterium tuberculosis growth inhibition in vitro. Microbes Infect/Institut Pasteur 2006; 8: 541–551.

de Haas CJ, van Leeuwen EM, van Bommel T, Verhoef J, van Kessel KP, van Strijp JA . Serum amyloid P component bound to gram-negative bacteria prevents lipopolysaccharide-mediated classical pathway complement activation. Infect Immun 2000; 68: 1753–1759.

Noursadeghi M, Bickerstaff MC, Gallimore JR, Herbert J, Cohen J, Pepys MB . Role of serum amyloid P component in bacterial infection: protection of the host or protection of the pathogen. Proc Natl Acad Sci U S A 2000; 97: 14584–14589.

Cox N, Pilling D, Gomer RH . Distinct Fcgamma receptors mediate the effect of serum amyloid p on neutrophil adhesion and fibrocyte differentiation. J Immunol 2014;193: 1701–1708.

Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol 2011; 43: 154–162.

Murray LA, Rosada R, Moreira AP, Joshi A, Kramer MS, Hesson DP et al. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS One 2010; 5: e9683.

Zhang W, Xu W, Xiong S . Macrophage differentiation and polarization via phosphatidylinositol 3-kinase/Akt-ERK signaling pathway conferred by serum amyloid P component. J Immunol 2011; 187: 1764–1777.

Castano AP, Lin SL, Surowy T, Nowlin BT, Turlapati SA, Patel T et al. Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo. Sci Transl Med 2009; 1: 5ra13.

Kirschning CJ, Unbehaun A, Fiedler G, Hallatschek W, Lamping N, Pfeil D et al. The transcriptional activation pattern of lipopolysaccharide binding protein (LBP) involving transcription factors AP-1 and C/EBP beta. Immunobiology 1997; 198: 124–135.

Wolk K, Witte E, Hoffmann U, Doecke WD, Endesfelder S, Asadullah K et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J Immunol 2007; 178: 5973–5981.

Kirschning C, Unbehaun A, Lamping N, Pfeil D, Herrmann F, Schumann RR . Control of transcriptional activation of the lipopolysaccharide binding protein (LBP) gene by proinflammatory cytokines. Cytokines Cell Mol Ther 1997; 3: 59–62.

Su GL, Dorko K, Strom SC, Nussler AK, Wang SC . CD14 expression and production by human hepatocytes. J Hepatol 1999; 31: 435–442.

Bas S, Gauthier BR, Spenato U, Stingelin S, Gabay C . CD14 is an acute-phase protein. J Immunol 2004; 172: 4470–4479.

Pan Z, Zhou L, Hetherington CJ, Zhang DE . Hepatocytes contribute to soluble CD14 production, and CD14 expression is differentially regulated in hepatocytes and monocytes. J Biol Chem 2000; 275: 36430–36435.

Liu S, Shapiro RA, Nie S, Zhu D, Vodovotz Y, Billiar TR . Characterization of rat CD14 promoter and its regulation by transcription factors AP1 and Sp family proteins in hepatocytes. Gene 2000; 250: 137–147.

Tissieres P, Dunn-Siegrist I, Schappi M, Elson G, Comte R, Nobre V et al. Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria. Blood 2008; 111: 2122–2131.

Tissieres P, Araud T, Ochoda A, Drifte G, Dunn-Siegrist I, Pugin J . Cooperation between PU.1 and CAAT/enhancer-binding protein beta is necessary to induce the expression of the MD-2 gene. J Biol Chem 2009; 284: 26261–26272.

Schumann RR, Kirschning CJ, Unbehaun A, Aberle HP, Knope HP, Lamping N et al. The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins. Mol Cell Biol 1996; 16: 3490–3503.

Weiss J . Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria. Biochem Soc Trans 2003; 31: 785–790.

Fan MH, Klein RD, Steinstraesser L, Merry AC, Nemzek JA, Remick DG et al. An essential role for lipopolysaccharide-binding protein in pulmonary innate immune responses. Shock 2002; 18: 248–254.

Jack RS, Fan X, Bernheiden M, Rune G, Ehlers M, Weber A et al. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 1997; 389: 742–745.

Yang KK, Dorner BG, Merkel U, Ryffel B, Schutt C, Golenbock D et al. Neutrophil influx in response to a peritoneal infection with Salmonella is delayed in lipopolysaccharide-binding protein or CD14-deficient mice. J Immunol 2002; 169: 4475–4480.

Knapp S, de Vos AF, Florquin S, Golenbock DT, van der Poll T . Lipopolysaccharide binding protein is an essential component of the innate immune response to Escherichia coli peritonitis in mice. Infect Immun 2003; 71: 6747–6753.

Le Roy D, Di Padova F, Tees R, Lengacher S, Landmann R, Glauser MP et al. Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP) protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP or the presentation of LPS/LBP complexes to CD14. J Immunol 1999; 162: 7454–7460.

Schumann RR . Old and new findings on lipopolysaccharide-binding protein: a soluble pattern-recognition molecule. Biochem Soc Trans 2011; 39: 989–993.

Vreugdenhil AC, Rousseau CH, Hartung T, Greve JW, van 't Veer C, Buurman WA . Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J Immunol 2003; 170: 1399–1405.

Weber JR, Freyer D, Alexander C, Schroder NW, Reiss A, Kuster C et al. Recognition of pneumococcal peptidoglycan: an expanded, pivotal role for LPS binding protein. Immunity 2003; 19: 269–279.

Schroder NW, Heine H, Alexander C, Manukyan M, Eckert J, Hamann L et al. Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. J Immunol 2004; 173: 2683–2691.

Schroder NW, Morath S, Alexander C, Hamann L, Hartung T, Zahringer U et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem 2003; 278: 15587–15594.

Branger J, Florquin S, Knapp S, Leemans JC, Pater JM, Speelman P et al. LPS-binding protein-deficient mice have an impaired defense against Gram-negative but not Gram-positive pneumonia. Int Immunol 2004; 16: 1605–1611.

Mueller M, Stamme C, Draing C, Hartung T, Seydel U, Schromm AB . Cell activation of human macrophages by lipoteichoic acid is strongly attenuated by lipopolysaccharide-binding protein. J Biol Chem 2006; 281: 31448–31456.

Hermann C, Spreitzer I, Schroder NW, Morath S, Lehner MD, Fischer W et al. Cytokine induction by purified lipoteichoic acids from various bacterial species—role of LBP, sCD14, CD14 and failure to induce IL-12 and subsequent IFN-gamma release. Eur J Immunol 2002: 32: 541–551.

Damien P, Cognasse F, Eyraud MA, Arthaud CA, Pozzetto B, Garraud O et al. LPS stimulation of purified human platelets is partly dependent on plasma soluble CD14 to secrete their main secreted product, soluble-CD40-Ligand. BMC Immunol 2015; 16: 3.

Moreno C, Merino J, Ramirez N, Echeverria A, Pastor F, Sanchez-Ibarrola A . Lipopolysaccharide needs soluble CD14 to interact with TLR4 in human monocytes depleted of membrane CD14. Microb Infect/Institut Pasteur 2004; 6: 990–995.

Asai Y, Makimura Y, Kawabata A, Ogawa T . Soluble CD14 discriminates slight structural differences between lipid as that lead to distinct host cell activation. J Immunol 2007; 179: 7674–7683.

Ohnishi T, Muroi M, Tanamoto K . Inhibitory effects of soluble MD-2 and soluble CD14 on bacterial growth. Microbiol Immunol 2010; 54: 74–80.

Kitchens RL, Thompson PA, Viriyakosol S, O'Keefe GE, Munford RS . Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. J Clin Invest 2001; 108: 485–493.

Jacque B, Stephan K, Smirnova I, Kim B, Gilling D, Poltorak A . Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS-induced lethality. Eur J Immunol 2006; 36: 3007–3016.

Ranoa DR, Kelley SL, Tapping RI . Human lipopolysaccharide-binding protein (LBP) and CD14 independently deliver triacylated lipoproteins to toll-like receptor 1 (TLR1) and TLR2 and enhance formation of the ternary signaling complex. J Biol Chem 2013; 288: 9729–9741.

Puertollano MA, Puertollano E, de Cienfuegos GA, de Pablo MA . Dietary antioxidants: immunity and host defense. Current Topics Med Chem 2011; 11: 1752–1766.

Wintergerst ES, Maggini S, Hornig DH . Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 2007; 51: 301–323.

Drakesmith H, Prentice AM . Hepcidin and the iron-infection axis. Science 2012;338: 768–772.

Gomme PT, McCann KB, Bertolini J . Transferrin: structure, function and potential therapeutic actions. Drug Discov Today 2005; 10: 267–273.

Zakin MM . Regulation of transferrin gene expression. FASEB J 1992; 6: 3253–3258.

Aisen P, Leibman A, Zweier J . Stoichiometric and site characteristics of the binding of iron to human transferrin. J Biol Chem 1978; 253: 1930–1937.

Eckenroth BE, Steere AN, Chasteen ND, Everse SJ, Mason AB . How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH. Proc Natl Acad Sci USA 2011; 108: 13089–13094.

Andres MT, Fierro JF . Antimicrobial mechanism of action of transferrins: selective inhibition of H+-ATPase. Antimicrob Agents Chemother 2010; 54: 4335–4342.

Lin L, Pantapalangkoor P, Tan B, Bruhn KW, Ho T, Nielsen T et al. Transferrin iron starvation therapy for lethal bacterial and fungal infections. J Infect Dis 2014; 10: 254–264.

Rooijakkers SH, Rasmussen SL, McGillivray SM, Bartnikas TB, Mason AB, Friedlander AM et al. Human transferrin confers serum resistance against Bacillus anthracis. J Biol Chem 2010; 285: 27609–27613.

von Bonsdorff L, Sahlstedt L, Ebeling F, Ruutu T, Parkkinen J . Apotransferrin administration prevents growth of Staphylococcus epidermidis in serum of stem cell transplant patients by binding of free iron. FEMS Immunol Med Microbiol 2003; 37: 45–51.

Barber MF, Elde NC . Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 2014, 346: 1362–1366.

Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004; 432: 917–921.

Wu H, Santoni-Rugiu E, Ralfkiaer E, Porse BT, Moser C, Hoiby N et al. Lipocalin 2 is protective against E. coli pneumonia. Respir Res 2010; 11: 96.

Bachman MA, Oyler JE, Burns SH, Caza M, Lepine F, Dozois CM et al. Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect Immun 2011; 79: 3309–3316.

Xu MJ, Feng D, Wu H, Wang H, Chan Y, Kolls J et al. Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy: a critical role for IL-6/STAT3. Hepatology 2015; 61: 692–702.

Bachman MA, Lenio S, Schmidt L, Oyler JE, Weiser JN . Interaction of lipocalin 2, transferrin, and siderophores determines the replicative niche of Klebsiella pneumoniae during pneumonia. mBio 2012; 3: pii: e00224–11.

Guglani L, Gopal R, Rangel-Moreno J, Junecko BF, Lin Y, Berger T et al. Lipocalin 2 regulates inflammation during pulmonary mycobacterial infections. PLoS One 2012; 7: e50052.

Sickinger S, Maier H, Konig S, Vallant N, Kofler M, Schumpp P et al. Lipocalin-2 as mediator of chemokine expression and granulocyte infiltration during ischemia and reperfusion. Transpl Int 2013; 26: 761–769.

Guo H, Jin D, Chen X . Lipocalin 2 is a regulator of macrophage polarization and NF-kappaB/STAT3 pathway activation. Mol Endocrinol 2014; 28: 1616–1628.

Cheng L, Xing H, Mao X, Li L, Li X, Li Q . Lipocalin-2 promotes m1 macrophages polarization in a mouse cardiac ischaemia-reperfusion injury model. Scand J Immunol 2015; 81: 31–38.

Rocha ER, Smith A, Smith CJ, Brock JH . Growth inhibition of Bacteroides fragilis by hemopexin: proteolytic degradation of hemopexin to overcome heme limitation. FEMS Microbiol Lett 2001; 199: 73–78.

Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassu AM et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Trans Med 2010; 2: 51ra71.

Liang X, Lin T, Sun G, Beasley-Topliffe L, Cavaillon JM, Warren HS . Hemopexin down-regulates LPS-induced proinflammatory cytokines from macrophages. J Leukocyte Biol 2009; 86: 229–235.

Lin T, Sammy F, Yang H, Thundivalappil S, Hellman J, Tracey KJ et al. Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation. J Immunol 2012; 189: 2017–2022.

Park CH, Valore EV, Waring AJ, Ganz T . Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: 7806–7810.

Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480: 147–150.

Ganz T . Hepcidin in iron metabolism. Curr Opin Hematol 2004; 11: 251–254.

Singh B, Arora S, Agrawal P, Gupta SK . Hepcidin: a novel peptide hormone regulating iron metabolism. Clin Chim Acta 2011; 412: 823–830.

Fish RJ, Neerman-Arbez M . Fibrinogen gene regulation. Thromb Haemost 2012; 108: 419–426.

Pahlman LI, Morgelin M, Kasetty G, Olin AI, Schmidtchen A, Herwald H . Antimicrobial activity of fibrinogen and fibrinogen-derived peptides–a novel link between coagulation and innate immunity. Thromb Haemost 2013; 109: 930–939.

Endo Y, Nakazawa N, Iwaki D, Takahashi M, Matsushita M, Fujita T . Interactions of ficolin and mannose-binding lectin with fibrinogen/fibrin augment the lectin complement pathway. J Innate Immun 2010; 2: 33–42.

Hoppe B . Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation. Thromb Haemost 2014; 112: 649–658.

Pluskota E, Soloviev DA, Szpak D, Weber C, Plow EF . Neutrophil apoptosis: selective regulation by different ligands of integrin alphaMbeta2. J Immunol 2008; 181: 3609–3619.

Solovjov DA, Pluskota E, Plow EF . Distinct roles for the alpha and beta subunits in the functions of integrin alphaMbeta2. J Biol Chem 2005; 280: 1336–1345.

Lishko VK, Kudryk B, Yakubenko VP, Yee VC, Ugarova TP . Regulated unmasking of the cryptic binding site for integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry 2002; 41: 12942–12951.

Orchekowski RP, Plescia J, Altieri DC, Bajt ML . AlphaMbeta2 (CD11b/CD18, Mac-1) integrin activation by a unique monoclonal antibody to alphaM I domain that is divalent cation-sensitive. J Leukocyte Biol 2000; 68: 641–649.

Flick MJ, Du X, Witte DP, Jirouskova M, Soloviev DA, Busuttil SJ et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest 2004; 113: 1596–1606.

Yan SR, Sapru K, Issekutz AC . The CD11/CD18 (beta2) integrins modulate neutrophil caspase activation and survival following TNF-alpha or endotoxin induced transendothelial migration. Immunol Cell Biol 2004; 82: 435–446.

Rubel C, Gomez S, Fernandez GC, Isturiz MA, Caamano J, Palermo MS . Fibrinogen-CD11b/CD18 interaction activates the NF-kappa B pathway and delays apoptosis in human neutrophils. Eur J Immunol 2003; 33: 1429–1438.

Rubel C, Fernandez GC, Rosa FA, Gomez S, Bompadre MB, Coso OA et al. Soluble fibrinogen modulates neutrophil functionality through the activation of an extracellular signal-regulated kinase-dependent pathway. J Immunol 2002; 168: 3527–3535.

Flick MJ, Du X, Degen JL . Fibrin(ogen)-alpha M beta 2 interactions regulate leukocyte function and innate immunity in vivo. Exp Biol Med (Maywood) 2004; 229: 1105–1110.

Andus T, Gross V, Tran-Thi TA, Schreiber G, Nagashima M, Heinrich PC . The biosynthesis of acute-phase proteins in primary cultures of rat hepatocytes. Eur J Biochem 1983; 133: 561–571.

Armstrong PB, Quigley JP . Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system. Dev Comp Immunol 1999; 23: 375–390.

Armstrong PB . Proteases and protease inhibitors: a balance of activities in host-pathogen interaction. Immunobiology 2006; 211: 263–281.

Hoijer MA, Melief MJ, Keck W, Hazenberg MP . Purification and characterization of N-acetylmuramyl-L-alanine amidase from human plasma using monoclonal antibodies. Biochim Biophy Acta 1996; 1289: 57–64.

Wang Z, Burke PA . Hepatocyte nuclear factor-4alpha interacts with other hepatocyte nuclear factors in regulating transthyretin gene expression. FEBS J 2010; 277: 4066–4075.

Shavva VS, Mogilenko DA, Dizhe EB, Oleinikova GN, Perevozchikov AP, Orlov SV . Hepatic nuclear factor 4alpha positively regulates complement C3 expression and does not interfere with TNFalpha-mediated stimulation of C3 expression in HepG2 cells. Gene 2013; 524: 187–192.

Schrem H, Klempnauer J, Borlak J . Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. Pharmacol Rev 2004; 56: 291–330.

Juan TS, Wilson DR, Wilde MD, Darlington GJ . Participation of the transcription factor C/EBP delta in the acute-phase regulation of the human gene for complement component C3. Proc Natl Acad Sci USA 1993; 90: 2584–2588.

Gonzalez S, Lopez-Larrea C . Characterization of the human C6 promoter: requirement of the CCAAT enhancer binding protein binding site for C6 gene promoter activity. J Immunol 1996; 157: 2282–2290.

Gonzalez S, Martinez-Borra J, Lopez-Larrea C . Cloning and characterization of human complement component C7 promoter. Genes Immun 2003; 4: 54–59.

Huang JH, Liao WS . Induction of the mouse serum amyloid A3 gene by cytokines requires both C/EBP family proteins and a novel constitutive nuclear factor. Mol Cell Biol 1994; 14: 4475–4484.

Dalmon J, Laurent M, Courtois G . The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. Mol Cell Biol 1993; 13: 1183–1193.

Burgess-Beusse BL, Darlington GJ . C/EBPalpha is critical for the neonatal acute-phase response to inflammation. Mol Cell Biol 1998; 18: 7269–7277.

Singh PP, Voleti B, Agrawal A . A novel RBP-J kappa-dependent switch from C/EBP beta to C/EBP zeta at the C/EBP binding site on the C-reactive protein promoter. J Immunol 2007; 178: 7302–7309.

Welm AL, Mackey SL, Timchenko LT, Darlington GJ, Timchenko NA . Translational induction of liver-enriched transcriptional inhibitory protein during acute phase response leads to repression of CCAAT/enhancer binding protein alpha mRNA. J Biol Chem 2000; 275: 27406–27413.

Cantwell CA, Sterneck E, Johnson PF . Interleukin-6-specific activation of the C/EBPdelta gene in hepatocytes is mediated by Stat3 and Sp1. Mol Cell Biol 1998; 18: 2108–2117.

Alam T, An MR, Papaconstantinou J . Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. J Biol Chem 1992; 267: 5021–5024.

Verschuur M, de Jong M, Felida L, de Maat MP, Vos HL . A hepatocyte nuclear factor-3 site in the fibrinogen beta promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent -148C/T polymorphism. J Biol Chem 2005; 280: 16763–16771.

Patel DN, King CA, Bailey SR, Holt JW, Venkatachalam K, Agrawal A et al. Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 2007; 282: 27229–27238.

Ray A, Ray BK . Serum amyloid A gene expression under acute-phase conditions involves participation of inducible C/EBP-beta and C/EBP-delta and their activation by phosphorylation. Mol Cel Biol 1994; 14: 4324–4332.

Liang SC, Nickerson-Nutter C, Pittman DD, Carrier Y, Goodwin DG, Shields KM et al. IL-22 induces an acute-phase response. J Immunol 2010; 185: 5531–5538.

Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S et al. In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology 2011; 54: 252–261.

Alonzi T, Maritano D, Gorgoni B, Rizzuto G, Libert C, Poli V . Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. Mol Cell Biol 2001; 21: 1621–1632.

Nishikawa T, Hagihara K, Serada S, Isobe T, Matsumura A, Song J et al. Transcriptional complex formation of c-Fos, STAT3, and hepatocyte NF-1 alpha is essential for cytokine-driven C-reactive protein gene expression. J Immunol 2008; 180: 3492–3501.

Hagihara K, Nishikawa T, Sugamata Y, Song J, Isobe T, Taga T et al. Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression. Genes Cells 2005; 10: 1051–1063.

Poli V, Mancini FP, Cortese R . IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell 1990;. 63: 643–653.

Yamada T, Tobita K, Osada S, Nishihara T, Imagawa M . CCAAT/enhancer-binding protein delta gene expression is mediated by APRF/STAT3. J Biochem 1997; 121: 731–738.

Mogilenko DA, Kudriavtsev IV, Shavva VS, Dizhe EB, Vilenskaya EG, Efremov AM et al. Peroxisome proliferator-activated receptor alpha positively regulates complement C3 expression but inhibits tumor necrosis factor alpha-mediated activation of C3 gene in mammalian hepatic-derived cells. J Biol Chem 2013; 288: 1726–1738.

Kramer F, Torzewski J, Kamenz J, Veit K, Hombach V, Dedio J et al. Interleukin-1beta stimulates acute phase response and C-reactive protein synthesis by inducing an NFkappaB- and C/EBPbeta-dependent autocrine interleukin-6 loop. Mol Immunol 2008; 45: 2678–2689.

Yoshida Y, Kumar A, Koyama Y, Peng H, Arman A, Boch JA et al. Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism. J Biol Chem 2004; 279: 1768–1776.

Agrawal A, Cha-Molstad H, Samols D, Kushner I . Transactivation of C-reactive protein by IL-6 requires synergistic interaction of CCAAT/enhancer binding protein beta (C/EBP beta) and Rel p50. J Immunol 2001; 166: 2378–2384.

Quinton LJ, Blahna MT, Jones MR, Allen E, Ferrari JD, Hilliard KL et al. Hepatocyte-specific mutation of both NF-kappaB RelA and STAT3 abrogates the acute phase response in mice. J Clin Invest 2012; 122: 1758–1763.

Mandrekar P, Ambade A, Lim A, Szabo G, Catalano D . An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 2011; 54: 2185–2197.

Obstfeld AE, Sugaru E, Thearle M, Francisco AM, Gayet C, Ginsberg HN et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 2010; 59: 916–925.

Chang B, Xu MJ, Zhou Z, Cai Y, Li M, Wang W et al. Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: an important role for CXCL1. Hepatology 2015; 62: 1070–1085.

Batra S, Cai S, Balamayooran G, Jeyaseelan S . Intrapulmonary administration of leukotriene B(4) augments neutrophil accumulation and responses in the lung to Klebsiella infection in CXCL1 knockout mice. J Immunol 2012; 188: 3458–3468.

Dziarski R, Gupta D . Review: mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity. Innate Immun 2010; 16: 168–174.

Boneca IG . Mammalian PGRPs in the spotlight. Cell Host Microbe 2009; 5: 109–111.

Deng M, Scott MJ, Loughran P, Gibson G, Sodhi C, Watkins S et al. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J Immunol 2013; 190: 5152–5160.

Herkel J, Jagemann B, Wiegard C, Lazaro JF, Lueth S, Kanzler S et al. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes. Hepatology 2003; 37: 1079–1085.

Bertolino P, Trescol-Biemont MC, Rabourdin-Combe C . Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. Eur J Immunol 1998; 28: 221–236.

Crispe IN . Hepatic T cells and liver tolerance. Nat Rev Immunol 2003; 3: 51–62.

Muhlbauer M, Fleck M, Schutz C, Weiss T, Froh M, Blank C et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol 2006; 45: 520–528.

Le Moine O, Deviere J, Devaster JM, Crusiaux A, Durand F, Bernuau J et al. Interleukin-6: an early marker of bacterial infection in decompensated cirrhosis. J Hepatol 1994; 20: 819–824.

Mackenzie I, Woodhouse J . C-reactive protein concentrations during bacteraemia: a comparison between patients with and without liver dysfunction. Intensive Care Med 2006; 32: 1344–1351.

Park WB, Lee KD, Lee CS, Jang HC, Kim HB, Lee HS et al. Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn Microbiol Infect Dis 2005; 51: 227–230.

Lemmers A, Gustot T, Durnez A, Evrard S, Moreno C, Quertinmont E et al. An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease. Clin Exp Immunol 2009; 156: 518–527.

Thomsen KL, Hebbard L, Glavind E, Clouston A, Vilstrup H, George J et al. Non-alcoholic steatohepatitis weakens the acute phase response to endotoxin in rats. Liver Int 2014; 34: 1584–1592.

Jepsen P, Vilstrup H, Mellemkjaer L, Thulstrup AM, Olsen JH, Baron JA et al. Prognosis of patients with a diagnosis of fatty liver–a registry-based cohort study. Hepato-gastroenterology 2003; 50: 2101–2104.

Dommett RM, Klein N, Turner MW . Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens 2006; 68: 193–209.

Keizer MP, Wouters D, Schlapbach LJ, Kuijpers TW . Restoration of MBL-deficiency: redefining the safety, efficacy and viability of MBL-substitution therapy. Mol Immunol 2014; 61: 174–184.