Loss of Pentameric Symmetry of C-reactive Protein Is Associated with Delayed Apoptosis of Human Neutrophils

Human neutrophil granulocytes die rapidly, and their survival is contingent upon rescue from programmed cell death by signals from the environment. Here we report that a novel signal for delaying neutrophil apoptosis is the classic acute phase reactant, C-reactive protein (CRP). However, this anti-apoptotic activity is expressed only when the cyclic pentameric structure of CRP is lost, resulting in formation of modified or monomeric CRP (mCRP), which may be formed in inflamed tissues. By contrast, native pentameric CRP and CRP peptides 77–82, 174–185, and 201–206 failed to affect neutrophil apoptosis. The apoptosis delaying action of mCRP was markedly attenuated by an antibody against the low affinity IgG immune complex receptor (CD16) but not by an anti-CD32 antibody. mCRP evoked a transient concurrent activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt signaling pathways, leading to inhibition of caspase-3 and consequently to delaying apoptosis. Consistently, pharmacological inhibition of either ERK or Akt reversed the anti-apoptotic action of mCRP; however, they did not produce additive inhibition. Thus, mCRP, but not pentameric CRP or peptides derived from CRP, promotes neutrophil survival and may therefore contribute to amplification of the inflammatory response. Human neutrophil granulocytes die rapidly, and their survival is contingent upon rescue from programmed cell death by signals from the environment. Here we report that a novel signal for delaying neutrophil apoptosis is the classic acute phase reactant, C-reactive protein (CRP). However, this anti-apoptotic activity is expressed only when the cyclic pentameric structure of CRP is lost, resulting in formation of modified or monomeric CRP (mCRP), which may be formed in inflamed tissues. By contrast, native pentameric CRP and CRP peptides 77–82, 174–185, and 201–206 failed to affect neutrophil apoptosis. The apoptosis delaying action of mCRP was markedly attenuated by an antibody against the low affinity IgG immune complex receptor (CD16) but not by an anti-CD32 antibody. mCRP evoked a transient concurrent activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt signaling pathways, leading to inhibition of caspase-3 and consequently to delaying apoptosis. Consistently, pharmacological inhibition of either ERK or Akt reversed the anti-apoptotic action of mCRP; however, they did not produce additive inhibition. Thus, mCRP, but not pentameric CRP or peptides derived from CRP, promotes neutrophil survival and may therefore contribute to amplification of the inflammatory response. Migration of neutrophil granulocytes into tissues during inflammation is intimately linked to their activation for functional activity as well as cell survival. Mature human neutrophils have the shortest life span among leukocytes and die rapidly via apoptosisin vitro and, apparently, in vivo (1Savill J.S. Wyllie A.H. Henson J.E. Walport M.J. Henson P.M. Haslett C. J. Clin. Invest. 1989; 83: 865-875Google Scholar, 2Colotta F., Re, F. Polentarutti N. Sozzani S. Mantovani A. Blood. 1992; 80: 2012-2020Google Scholar, 3Whyte M.K.B. Meagher L.C. Macdermot J. Haslett C. J. Immunol. 1993; 150: 5124-5134Google Scholar, 4Lee A. Whyte M.K.B. Haslett C. J. Leukocyte Biol. 1993; 54: 283-288Google Scholar). Neutrophils undergoing apoptosis lose CD16 (FcγRIII) expression (5Dransfield I. Buckle A. Savill J.S. McDowall A. Haslett C. Hogg N. J. Immunol. 1994; 153: 1254-1263Google Scholar,6Homburg C.H. de Haas M. von dem Borne Jr., A.E.G. Verhoeven A.J. Reutelingsperger C.P.M. Roos D. Blood. 1995; 85: 532-540Google Scholar) and show a reduced ability to respond to chemoattractants (3Whyte M.K.B. Meagher L.C. Macdermot J. Haslett C. J. Immunol. 1993; 150: 5124-5134Google Scholar, 4Lee A. Whyte M.K.B. Haslett C. J. Leukocyte Biol. 1993; 54: 283-288Google Scholar). This constitutively expressed program may serve to render neutrophils functionally ineffective before their removal by scavenger macrophages (3Whyte M.K.B. Meagher L.C. Macdermot J. Haslett C. J. Immunol. 1993; 150: 5124-5134Google Scholar). However, the life span of mature neutrophils can be extended significantly within the inflammatory microenvironment by bacterial products (2Colotta F., Re, F. Polentarutti N. Sozzani S. Mantovani A. Blood. 1992; 80: 2012-2020Google Scholar, 4Lee A. Whyte M.K.B. Haslett C. J. Leukocyte Biol. 1993; 54: 283-288Google Scholar), pro-inflammatory cytokines, including interleukin 2, interferon γ and granulocyte macrophage-colony-stimulating factor (4Lee A. Whyte M.K.B. Haslett C. J. Leukocyte Biol. 1993; 54: 283-288Google Scholar), and glucocorticoids (7Liles W.C. Dale D.C. Klebanoff S.J. Blood. 1995; 86: 3181-3188Google Scholar). The regulation of neutrophil apoptosis during the acute phase of inflammation is less well defined, yet it is critical to the optimal expression and resolution of inflammation. C-reactive protein (CRP), 1The abbreviations used are: CRP, C-reactive protein; mCRP, modified or monomeric CRP; rmCRP, recombinant form of mCRP; Ab, antibody; LPS, lipopolysaccharide; ERK 1/2, extracellular-signal regulated kinase 1/2; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; PS, phosphatidylserine; BAD, Bcl-2 associated death protein; AMC, aminomethylcoumarin. a prototypical acute phase reactant, is a member of the pentraxin family of highly conserved cyclic pentameric proteins (8Kushner I. Methods Enzymol. 1988; 163: 373-383Google Scholar, 9Gabay C. Kushner I. N. Engl. J. Med. 1999; 340: 448-454Google Scholar). Despite extensive studies spanning several decades, the exact role and mechanism of action of CRP as a modulator of inflammation has not been well defined, as both pro- and anti-inflammatory actions have been reported (8Kushner I. Methods Enzymol. 1988; 163: 373-383Google Scholar, 9Gabay C. Kushner I. N. Engl. J. Med. 1999; 340: 448-454Google Scholar, 10Mold C. Nakayama S. Holzer T.J. Gewurz H. Du Clos T.W. J. Exp. Med. 1981; 154: 1703-1708Google Scholar, 11Siegel J. Rent R. Gewurz H. J. Exp. Med. 1974; 140: 631-647Google Scholar, 12Ballou S.P. Lozanski G. Cytokine. 1992; 4: 361-368Google Scholar, 13Heuertz R.M. Webster R.O. Mol. Med. Today. 1997; : 539-545Google Scholar, 14Xia D. Samols D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2575-2580Google Scholar, 15Zouki C. Beauchamp M. Baron C. Filep J.G. J. Clin. Invest. 1997; 100: 522-529Google Scholar). These apparently contradictory results might be explained by formation of distinct species of CRP during inflammation. In general, the effects of native, pentameric CRP on neutrophils are largely inhibitory. CRP binds primarily to the low affinity IgG FcγRIIa (CD32) and to some extent to the high affinity IgG FcγRI (CD64) (16Bharadwaj D Stein M.P. Volzer M. Mold C. Du Clos T.W. J. Exp. Med. 1999; 190: 585-590Google Scholar, 17Marnell L.L. Mold C. Volzer M.A. Burlingame R.W. Du Clos T.W. J. Immunol. 1995; 155: 2185-2193Google Scholar, 18Stein M.P. Edberg J.C. Kimberly R.P. Mangan E.K. Bharadwaj D. Mold C. Du Clos T.W. J. Clin. Invest. 2000; 105: 369-376Google Scholar). Neutrophils exposed to native CRP show depressed functional activities, including degranulation (19Filep J. Földes-Filep E. Life. Sci. 1989; 44: 517-524Google Scholar), generation of superoxide by the inducible respiratory burst (19Filep J. Földes-Filep E. Life. Sci. 1989; 44: 517-524Google Scholar), adherence to endothelial cells (15Zouki C. Beauchamp M. Baron C. Filep J.G. J. Clin. Invest. 1997; 100: 522-529Google Scholar), and migration into tissues (13Heuertz R.M. Webster R.O. Mol. Med. Today. 1997; : 539-545Google Scholar). Conformationally altered and/or proteolytic forms of CRP express several epitopes that are not present on native CRP (20Ying S-C. Gewurz H. Kinoshita C.M. Potempa L.A. Siegel J.N. J. Immunol. 1989; 143: 221-228Google Scholar) and display properties distinct from those of native CRP (21Potempa L.A. Siegel J.N. Fiedel B.A. Potempa R.T. Gewurz H. Mol. Immunol. 1987; 24: 531-541Google Scholar). Native, pentameric CRP can be dissociated into free subunits in vitro (21Potempa L.A. Siegel J.N. Fiedel B.A. Potempa R.T. Gewurz H. Mol. Immunol. 1987; 24: 531-541Google Scholar). These subunits expressing several neoepitopes are referred to as modified or monomeric CRP (mCRP). mCRP antigens were detected in inflamed rabbit tissues (22Rees R.F. Gewurz H. Siegel J.N. Coon J. Potempa L.A. Clin. Immunol. Immunopathol. 1988; 48: 95-107Google Scholar) as well as in the wall of human normal blood vessels (23Diehl E.E. Haines G.K. Radosevich J.A. Potempa L.A. Am. J. Med. Sci. 2000; 319: 79-83Google Scholar). Unlike native CRP, mCRP binds to the low affinity IgG immune complex FcγRIIIb 2G. P. Schneider, R. M. Heuertz, L. A. Potempa, and R. O. Webster, personal communication. and enhances neutrophil adhesiveness to endothelial cells via up-regulation of the expression of CD11b/C18 on the neutrophil surface (24Zouki C. Haas B. Chan J.S.D. Potempa L.A. Filep J.G. J. Immunol. 2001; 167: 5355-5361Google Scholar). Exposure of CRP to membrane-bound serine proteases leads to cleavage of biologically active peptides, which mimic the actions of native CRP on neutrophil chemotaxis (25Shephard E.G. Anderson R. Rosen O. Myer M.S. Friedkin M. Strachan A.F. de Beer F.C. J. Immunol. 1990; 145: 1469-1476Google Scholar) and adhesion to endothelial cells (15Zouki C. Beauchamp M. Baron C. Filep J.G. J. Clin. Invest. 1997; 100: 522-529Google Scholar). In this study, we investigated whether CRP, mCRP, or peptides derived from CRP could prolong neutrophil life span via inhibition of apoptosis. High purity (>99%) human native CRP (Calbiochem) was stored in buffers containing CaCl2 to prevent the spontaneous formation of monomeric CRP from the native CRP pentamer. mCRP was prepared from native CRP by urea chelation (21Potempa L.A. Siegel J.N. Fiedel B.A. Potempa R.T. Gewurz H. Mol. Immunol. 1987; 24: 531-541Google Scholar). By electron microscopy analysis, mCRP molecules in the absence of added salt associates into a diffuse matrix very distinct from the annular pentameric disk that is defined for native CRP (27Motie M. Brockmeister S. Potempa L.A. J. Immunol. 1996; 156: 4435-4441Google Scholar). The secondary structure of native CRP has been estimated using x-ray crystallography (28Shrive A.K. Cheetham G.M.T. Holden D. Myles D.A.A. Turnell W.G. Volanakis J.E. Pepys M.B. Bloomer A.C. Greenhough T.J. Nat. Struct. Biol. 1996; 3: 346-354Google Scholar) and Fourier transform infrared spectroscopy (29Dong A. Caughey W.S. DuClos T.W. J. Biol. Chem. 1994; 269: 6424-6430Google Scholar) as 50% β-sheet, 12% helix, 24% β-turn, and 14% unordered structure. A preliminary evaluation of mCRP secondary structure using circular dichroism and a self-consistent method (Selcon) for estimating structures (30Sreerama N. Woody R.W. Anal. Biochem. 1993; 209: 32-44Google Scholar) revealed mCRP to have 50–51% helix, 2–12% β-sheet, 20–23% β-turn, and 12–20% random structure. These data indicate that a significant secondary structural change occurs when mCRP is formed from CRP, changing from predominantly β-sheet structure to an α-helical structure. A recombinant form of mCRP (rmCRP) with both cysteine residues mutated to alanine residues (i.e. Cys36→ Ala; Cys97 → Ala) and with an added N-terminal formylmethionine residue was expressed in Escherichia coliand was isolated from inclusion bodies to >95% purity (26Potempa, L. A., Liao, H., and Crump, B. L. (February 23, 1999) U. S. Patent 5,874,238.Google Scholar). To enhance solubility, rmCRP was acylated with maleic anhydride or citraconic rmCRP was with mCRP from the native CRP by urea chelation in the that both rmCRP and mCRP proteins protein with an of to that of a native CRP that rmCRP the of residues of protein as mCRP with the of alanine residues of rmCRP with of mCRP, cysteine residues in rmCRP cysteine residues of mCRP and residues of rmCRP with in mCRP, the in The N-terminal of rmCRP with an a that to the for the CRP G. E. J. Biol. Chem. Scholar, P. J. Biol. Chem. Scholar). to the of the CRP or (20Ying S-C. Gewurz H. Kinoshita C.M. Potempa L.A. Siegel J.N. J. Immunol. 1989; 143: 221-228Google Scholar) with the and affinity to mCRP, rmCRP M.J. Siegel J.N. Potempa L.A. Gewurz H. Anderson B. J. Immunol. Scholar), and acylated forms of preliminary on a mCRP and rmCRP and acylated forms of rmCRP in neutrophil apoptosis by and of the and the in results in this report were with maleic CRP peptides 77–82, 174–185, and 201–206 were from The of CRP, mCRP, rmCRP, and CRP were the to of the Neutrophils were isolated from blood of and not for before the (15Zouki C. Beauchamp M. Baron C. Filep J.G. J. Clin. Invest. 1997; 100: 522-529Google Scholar). The was by the of the Neutrophils purity were in salt with and with native or modified CRP or peptides derived from CRP in on a in In neutrophils were with or the for before of the cells were in salt before in the of cells was by neutrophils for for apoptosis of cell or on a J.G. Baron C. S. C. Chan J.S.D. Blood. 1996; Scholar). were with for of apoptosis was as the of cells with I. G. F. J. Immunol. Scholar) and I. C. H. Reutelingsperger C. J. Immunol. 1995; Scholar). Neutrophils were in of in before of was using a were neutrophils were in of containing a of for and with before by was by using cleavage was by of by S. S.J. Blood. 1994; Scholar) and J.G. Baron C. S. C. Chan J.S.D. Blood. 1996; Scholar). the data are reported as the of low was from and in containing A for and to in for J.G. Baron C. S. C. Chan J.S.D. Blood. 1996; Scholar). with was by for prepared from were for in of containing of from was using a with and of and of was by using a antibody that both the and the of the active were prepared by neutrophils in of and of ERK 1/2, MAPK, and Akt was using the ERK 1/2, MAPK, and Akt as C. Chan J.S.D. Filep J.G. J. 2001; Scholar). are expressed as were by of using by to were significant for neutrophils of apoptosis including of by in cell and cleavage of resulting in within of CRP the of of the and The to neutrophil apoptosis by 50% was and The inhibition that can be with mCRP was to that with cells a in and cell were in of neutrophils by By contrast, native CRP CRP 201–206 significantly and the of cells with not CRP peptides and were ineffective not Thus, among the CRP only mCRP to apoptosis in the action of mCRP can be in an containing an of native mCRP reduced the of neutrophils from to or in the absence or of native CRP, of neutrophil apoptosis. of neutrophils in of neutrophils were prepared and of neutrophils and in vitro for in the absence or of mCRP or and of the effects of mCRP on of of neutrophil were prepared and for and or were for are the for using neutrophils from with is reported as the of cleavage products to expressed as the of with neutrophils isolated from blood with mCRP cleavage in neutrophils in for The of is for The and of are on the The results are of is to be a of we a of Neutrophils for a in the of low from a of isolated to Neutrophils with mCRP in the of low The of mCRP was with an of the ability of mCRP to in neutrophils The effects of and mCRP were with those of used to CD16 and as to the IgG receptor for the action of in and of neutrophils with were markedly attenuated in the of the anti-CD32 the the mCRP inhibition of the by neutrophil apoptosis not To the signaling that the action of mCRP, we the activation of to cell survival. Neutrophils with mCRP a and in of ERK and Akt to a and of both ERK and Akt was in a The of ERK and Akt by is for In vitro of neutrophils was associated with a activation of was detected as as of and was not by either mCRP or To the role of and in neutrophil we used the kinase the PI of Akt and the of neutrophil significantly the of cells with and the of neutrophils By contrast, both and attenuated the actions of mCRP, was The effects of and were not additive the mCRP is a of mCRP with did not in a of inhibition of neutrophil those with mCRP or activity was in isolated in vitro of neutrophils for significant in caspase-3 formation and activity of was by which a in the active form of caspase-3 of as well as caspase-3 activity were reduced by mCRP in a a and and attenuated the caspase-3 action of mCRP However, was not not with the of and to apoptosis to be the normal for and cell survival is contingent upon rescue of cells from programmed cell death by signals from the environment. in this report that a novel signal for delaying neutrophil apoptosis is the prototypical acute phase However, this action is in native CRP and is expressed only when the pentameric structure and a A of that distinct species of CRP are formed during inflammation. native CRP is and by into the blood (8Kushner I. Methods Enzymol. 1988; 163: 373-383Google Scholar, 9Gabay C. Kushner I. N. Engl. J. Med. 1999; 340: 448-454Google Scholar). CRP can be dissociated into free subunits in vitro and is apparently formed in vivo by a yet studies that of native CRP to and of the subunits of native CRP, leading to of an Biochem. 2001; Scholar). residues of native CRP residues and (28Shrive A.K. Cheetham G.M.T. Holden D. Myles D.A.A. Turnell W.G. Volanakis J.E. Pepys M.B. Bloomer A.C. Greenhough T.J. Nat. Struct. Biol. 1996; 3: 346-354Google Scholar), the of which is a of mCRP (20Ying S-C. Gewurz H. Kinoshita C.M. Potempa L.A. Siegel J.N. J. Immunol. 1989; 143: 221-228Google Scholar). The properties of the free subunits of CRP formed in vivo have not yet been mCRP epitopes have been reported in tissues (23Diehl E.E. Haines G.K. Radosevich J.A. Potempa L.A. Am. J. Med. Sci. 2000; 319: 79-83Google Scholar), inflamed rabbit and (22Rees R.F. Gewurz H. Siegel J.N. Coon J. Potempa L.A. Clin. Immunol. Immunopathol. 1988; 48: 95-107Google Scholar), N. C. J. 1995; Scholar), and cells D. 1997; Scholar). In the for CRP is expressed in blood cells N. C. J. 1995; Scholar, L.L. J. Exp. Med. Scholar), macrophages J. Immunol. 1996; 156: Scholar), cells D. 1997; Scholar), and cells of the respiratory J.N. J.N. 2001; Scholar). the mCRP used in the present studies may be not to a form of CRP in tissues and cells the CRP and/or mCRP may be or of in CRP and mCRP, resulting in the of biologically active peptides S. N. H. S. J. Biol. Chem. 1987; Scholar). mCRP is to is the native CRP C.M. Siegel N. Potempa L.A. H. Gewurz H. 1989; Scholar). In studies we show that mCRP, but not native CRP or peptides derived from CRP, neutrophil in the of native The mCRP action was low with the of neutrophils to mCRP resulting in neutrophil survival in Thus, mCRP an anti-apoptotic to those of granulocyte macrophage-colony-stimulating or (2Colotta F., Re, F. Polentarutti N. Sozzani S. Mantovani A. Blood. 1992; 80: 2012-2020Google Scholar, 4Lee A. Whyte M.K.B. Haslett C. J. Leukocyte Biol. 1993; 54: 283-288Google Scholar, W.C. Dale D.C. Klebanoff S.J. Blood. 1995; 86: 3181-3188Google Scholar). results that this action of mCRP is predominantly the low affinity immune complex IgG FcγRIIIb for the Ab, but not anti-CD32 Ab, reversed the anti-apoptotic action of These are with receptor studies FcγRIIIb as the for mCRP on human we the that the mCRP may be some yet cell surface is that mCRP might the low affinity IgG FcγRIIa (CD32) or the high affinity IgG FcγRI native CRP, which binds to (16Bharadwaj D Stein M.P. Volzer M. Mold C. Du Clos T.W. J. Exp. Med. 1999; 190: 585-590Google Scholar, 17Marnell L.L. Mold C. Volzer M.A. Burlingame R.W. Du Clos T.W. J. Immunol. 1995; 155: 2185-2193Google Scholar, 18Stein M.P. Edberg J.C. Kimberly R.P. Mangan E.K. Bharadwaj D. Mold C. Du Clos T.W. J. Clin. Invest. 2000; 105: 369-376Google Scholar), did not affect significantly of neutrophil apoptosis. neutrophils lose their surface FcγRIIIb during apoptosis (5Dransfield I. Buckle A. Savill J.S. McDowall A. Haslett C. Hogg N. J. Immunol. 1994; 153: 1254-1263Google Scholar, C.H. de Haas M. von dem Borne Jr., A.E.G. Verhoeven A.J. Reutelingsperger C.P.M. Roos D. Blood. 1995; 85: 532-540Google Scholar), which are of an anti-apoptotic signal as in the present The for peptides derived from CRP have not been to the in the actions of native CRP and peptides 77–82, 174–185, and 201–206 15Zouki C. Beauchamp M. Baron C. Filep J.G. J. Clin. Invest. 1997; 100: 522-529Google and L. A., Liao, H., and Crump, B. L. (February 23, 1999) U. S. Patent 5,874,238.Google and the present of the studies have reported the effects of and ERK or PI on apoptosis. In general, to both ERK and PI to programmed cell death M. J. 1995; Scholar, J.A. Henson P.M. J. Biol. Chem. Scholar, M.J. J.A. R. A. J. Immunol. 2000; Scholar, R. 1995; Scholar). Akt the anti-apoptotic action of PI H. M.J. 1997; Scholar, A. P. E. C. P. J. G. 1997; Scholar). with J.A. Henson P.M. J. Biol. Chem. Scholar), that spontaneous apoptosis in human neutrophils is associated with activation of and can be reversed by the of leads to cleavage of active of the of apoptosis. of neutrophils with mCRP to and activation of both ERK and In the present study, ERK PI inhibition could inhibition of caspase-3 activation and the of an signaling mechanism of PI and ERK inhibition did not the effects of mCRP on apoptosis. In of in neutrophils undergoing spontaneous apoptosis. This indicate that may of and are not in delaying apoptosis. by the FcγRIIIb leads to and of G. C. J. Leukocyte Biol. Scholar). kinase activation can to activation of ERK the (24Zouki C. Haas B. Chan J.S.D. Potempa L.A. Filep J.G. J. Immunol. 2001; 167: 5355-5361Google Scholar) or activation of PI and as was reported for granulocyte macrophage-colony-stimulating signaling in neutrophils M.J. J.A. R. A. J. Immunol. 2000; Scholar). Akt has been to a of the activation of the N. E. S. J.C. Scholar). results indicate that inhibition of the signaling results in inhibition of cleavage of and caspase-3 mCRP could apoptosis by caspase-3 via activation of Akt and and of FcγRIIa and FcγRIIIb was to transient activation of Akt PI in human neutrophils B. M. B.A. M. J. Biol. Chem. 1997; Scholar). However, native CRP, which binds to FcγRIIa but not to did not affect significantly of neutrophil apoptosis. This that Akt activation may not be to neutrophil of both the ERK and PI 3-kinase/Akt is to neutrophil survival. we reported that native CRP not ERK in neutrophils (24Zouki C. Haas B. Chan J.S.D. Potempa L.A. Filep J.G. J. Immunol. 2001; 167: 5355-5361Google Scholar). of neutrophil apoptosis is concurrent activation of ERK and PI 3-kinase/Akt C. L. J. Immunol. 2000; Scholar). Akt can BAD, a member of the Bcl-2 family E. J. J. S.J. 1995; 80: Scholar). from the anti-apoptotic effects of the Bcl-2 family proteins B. M. B.A. M. J. Biol. Chem. 1997; Scholar). These results that mCRP of the ERK and PI in to caspase-3 activation via regulation of expression of anti-apoptotic and/or by to the neutrophil These to be and are in results may have to neutrophil survival for into inflamed tissues. native CRP not neutrophil it binds to the surface of cells and the cell from the of the complex D. S.J. N. J. Exp. Med. 2000; Scholar), of the of mCRP with neutrophils not only to neutrophil activation and of adhesion (24Zouki C. Haas B. Chan J.S.D. Potempa L.A. Filep J.G. J. Immunol. 2001; 167: 5355-5361Google Scholar) but to of neutrophil the acute inflammatory response. that endothelial may in of mCRP that is expressed in the of blood vessels (23Diehl E.E. Haines G.K. Radosevich J.A. Potempa L.A. Am. J. Med. Sci. 2000; 319: 79-83Google Scholar), and or may to de formation of mCRP the inflamed of mCRP may the of resulting in formation of CRP peptides 77–82, 174–185, and native pentameric CRP, peptides of neutrophil they might of neutrophils (15Zouki C. Beauchamp M. Baron C. Filep J.G. J. Clin. Invest. 1997; 100: 522-529Google Scholar, S. N. H. S. J. Biol. Chem. 1987; Scholar), to of the inflammatory and resolution of inflammation. In results show that structural in the acute phase protein CRP can prolong neutrophil of pentameric in CRP is associated with of a novel apoptosis delaying in This action is in via activation of the low affinity IgG immune complex receptor (CD16) of the PI 3-kinase/Akt and signaling pathways, leading to inhibition of caspase-3 Thus, mCRP, but not native CRP or peptides derived from CRP, promotes neutrophil survival and may therefore contribute to amplification of the inflammatory response.