Immunology Today, voL 8, No. 11, 1987
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Platelet-adivating factor and cellular ....... immune responses Platelet-activating factor is a phospholipid mediator of the allergic reaction that is a potent stimulator of acute inflammatory processes. It is produced by various inflammatory cells upon activation by immune or nonimmune stimuli. As Pierre Braquet and Marek Rola-Plesz~pynskireview here, evidence is now accumulating that platelet-activating factor is a component in the regulation of cellular immune responses. During the 1960s, rabbit platelets were found to release histamine by a mechanism that was leukocyte- and antigen-dependent 1-3. The leukocytes were thought to provide a factor actively released by a calcium- and temperature-dependent process4,5; later, Benveniste et a/. 6.7, described the methodology to obtain this substance which they termed platelet-activating factor (PAF)*. They initiated its characterization and showed that it was released from rabbit basophils by an IgEdependent process, while subsequent structural elucidation demonstrated that PAF is 1-alkyl-2(R)-acetyl-glycero3-phosphocholine 8.9, a phospholipid sensitive to phospholipase A2 (Refs 8,10,11). The two principal molecular species of PAF produced by human neutrophils or rabbit basophils have a hexadecyl or octadecyl alkyl moiety, but more sophisticated separation techniques have demonstrated that PAF is composed of at least 16 molecular species containing saturated or unsaturated alkyl or acyl chains, or even a polar head group other than choline12,13 PAF is a potent mediator of anaphylaxis and hyperreactivity and may be involved in shock, graft rejection, HU:L'I:~.II¢IlII~.
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central nervous system (CNS) disorders (reviewed in Refs 14-18). Here, we concentrate on the data that show that PAF is also a potent modulator of the immune response.
PierreBr .et andHarek the eosinophil chemotactic factor of anaphylaxis (ECF-A). Endothelial cells release PAF in response to A23187, thrombin, vasopressin, angiotensin II, anti-factor VIII and interleukin 1 (IL-1). Even the bacterium E. coil was recently shown to produce PAF27. Generally, lymphocytes are unable to produce PAF, although they can produce 2-1yso-PAF when stimulated with A23187, so their failure to produce PAF may be due to the lack of acetyl transferase2s. Under specific circumstances, however, they may be stimulated to synthesize or activate acetyl transferase and thus produce PAF: large granular lymphocytes release PAF following Fc receptor stimulation z9 and a series of human leukemic cell lines of B- and T-cell origin, as well as Epstein-Barr virus-transformed lyml~hoblastoid cell lines, release PAFlike material following stimulation with A23187 acetyl CoA or phytohaemagglutinin (PHA)3o. Many of the cells or tissues producing PAF are themselves targets of PAF-induced bioactions 31-34. Often, specific receptors, or at least binding sites, for PAF have been identified (using radiolabelled PAF) (reviewed in Refs 35, 36). The discovery and development of PAF receptor-specific antagonists has greatly facilitated research in this field by indicating the circumstances in which PAF mediates the observed pathophysiological effects (reviewed in Refs 35, 37, 38). Direct effects of PAFon the immuneresponse
"-: .... :" %31V!~II II~. . .IJUL~IIL .... p r oi i'l flamm a tory CIILUVILIL-~J, . . . . . . . . . . r/-~r u' -l l doubtediy participates in the complex system of host defences. Using PAF receptor antagonists and agonists, recent work has focused on the potential of PAF for modulating cellular immune responses (Fig. 3). When PAF was added to human peripheral blood
Cell sourcesof PAF
Cellular origins of PAF are numerous6,19-26 (Fig. 2), although the origin of PAF during stress and inflammation is unknown. Sensitized basophils and mast cells release PAF in response to antigen or anti-lgE challenge. Monocytes and rnacrophages respond to phagocytic stimuli such as bacteria, opsonized zymosan or immune complexes, and to the calcium ionophore A23187, while neutrophils respond additionally to phorbol esters and the chemotactic agents CSa, CSa-des-Arg and formylmethionyl-leucyl-phenylaianine (FMLP). Eosinophils also respond to A23187, CSa and FMLP, and, in addition, to
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*BothPAF-acether(ace-for acetateandetherfor thealkylbond)andAGEPC (acetylglyceryletherphosphorylcholine)havebeenusedin the literatureto indicate PAF. Here, 1-O-octadecyl (or hexadecyl)-2(R)-acetyl-glycero-3phosphorylcholinewill besimplynamedPAF(Fig.1).
Institut Henri Beaufour ResearchLaboratories, 17 Avenue Descartes, F-92350 Le Plessis-Robinson,France; and 1ImmunologyDivision, Department of Pediatrics,Universityof Sherbrooke,Sherbrooke,QCJ1H 5N4, Canada (~) 1987, ElsevierPublications,Cambridge 0167-4919187/$02.00
Fig.1. Chemicalstructureof(R)and(S)PAF.
345
Immuno!ogy Today, voI. 8, No. # !, 1987
CheIOt I ¢ t
faN:t,~s
Eosi~l)hil
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'
Q
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Platelet-adivating factor and cellular ....... immune responses Platelet-activating factor is a phospholipid mediator of the allergic reaction that is a potent stimulator of acute inflammatory processes. It is produced by various inflammatory cells upon activation by immune or nonimmune stimuli. As Pierre Braquet and Marek Rola-Plesz~pynskireview here, evidence is now accumulating that platelet-activating factor is a component in the regulation of cellular immune responses. During the 1960s, rabbit platelets were found to release histamine by a mechanism that was leukocyte- and antigen-dependent 1-3. The leukocytes were thought to provide a factor actively released by a calcium- and temperature-dependent process4,5; later, Benveniste et a/. 6.7, described the methodology to obtain this substance which they termed platelet-activating factor (PAF)*. They initiated its characterization and showed that it was released from rabbit basophils by an IgEdependent process, while subsequent structural elucidation demonstrated that PAF is 1-alkyl-2(R)-acetyl-glycero3-phosphocholine 8.9, a phospholipid sensitive to phospholipase A2 (Refs 8,10,11). The two principal molecular species of PAF produced by human neutrophils or rabbit basophils have a hexadecyl or octadecyl alkyl moiety, but more sophisticated separation techniques have demonstrated that PAF is composed of at least 16 molecular species containing saturated or unsaturated alkyl or acyl chains, or even a polar head group other than choline12,13 PAF is a potent mediator of anaphylaxis and hyperreactivity and may be involved in shock, graft rejection, HU:L'I:~.II¢IlII~.
UI3UIU~I3,
UVUIIII~JIClIILClLIUil
dllU
L~ll.dl|i
central nervous system (CNS) disorders (reviewed in Refs 14-18). Here, we concentrate on the data that show that PAF is also a potent modulator of the immune response.
PierreBr .et andHarek the eosinophil chemotactic factor of anaphylaxis (ECF-A). Endothelial cells release PAF in response to A23187, thrombin, vasopressin, angiotensin II, anti-factor VIII and interleukin 1 (IL-1). Even the bacterium E. coil was recently shown to produce PAF27. Generally, lymphocytes are unable to produce PAF, although they can produce 2-1yso-PAF when stimulated with A23187, so their failure to produce PAF may be due to the lack of acetyl transferase2s. Under specific circumstances, however, they may be stimulated to synthesize or activate acetyl transferase and thus produce PAF: large granular lymphocytes release PAF following Fc receptor stimulation z9 and a series of human leukemic cell lines of B- and T-cell origin, as well as Epstein-Barr virus-transformed lyml~hoblastoid cell lines, release PAFlike material following stimulation with A23187 acetyl CoA or phytohaemagglutinin (PHA)3o. Many of the cells or tissues producing PAF are themselves targets of PAF-induced bioactions 31-34. Often, specific receptors, or at least binding sites, for PAF have been identified (using radiolabelled PAF) (reviewed in Refs 35, 36). The discovery and development of PAF receptor-specific antagonists has greatly facilitated research in this field by indicating the circumstances in which PAF mediates the observed pathophysiological effects (reviewed in Refs 35, 37, 38). Direct effects of PAFon the immuneresponse
"-: .... :" %31V!~II II~. . .IJUL~IIL .... p r oi i'l flamm a tory CIILUVILIL-~J, . . . . . . . . . . r/-~r u' -l l doubtediy participates in the complex system of host defences. Using PAF receptor antagonists and agonists, recent work has focused on the potential of PAF for modulating cellular immune responses (Fig. 3). When PAF was added to human peripheral blood
Cell sourcesof PAF
Cellular origins of PAF are numerous6,19-26 (Fig. 2), although the origin of PAF during stress and inflammation is unknown. Sensitized basophils and mast cells release PAF in response to antigen or anti-lgE challenge. Monocytes and rnacrophages respond to phagocytic stimuli such as bacteria, opsonized zymosan or immune complexes, and to the calcium ionophore A23187, while neutrophils respond additionally to phorbol esters and the chemotactic agents CSa, CSa-des-Arg and formylmethionyl-leucyl-phenylaianine (FMLP). Eosinophils also respond to A23187, CSa and FMLP, and, in addition, to
CH3 I
H3C CH, O eO..l~
H H ',, ~I H
u n
o" cO;: ' H
CH3 O e O . IP H 0 i 0 s''~
,
, - c3\, _ ,.c - - " o 's' ~'CH3/-O
*BothPAF-acether(ace-for acetateandetherfor thealkylbond)andAGEPC (acetylglyceryletherphosphorylcholine)havebeenusedin the literatureto indicate PAF. Here, 1-O-octadecyl (or hexadecyl)-2(R)-acetyl-glycero-3phosphorylcholinewill besimplynamedPAF(Fig.1).
Institut Henri Beaufour ResearchLaboratories, 17 Avenue Descartes, F-92350 Le Plessis-Robinson,France; and 1ImmunologyDivision, Department of Pediatrics,Universityof Sherbrooke,Sherbrooke,QCJ1H 5N4, Canada (~) 1987, ElsevierPublications,Cambridge 0167-4919187/$02.00
Fig.1. Chemicalstructureof(R)and(S)PAF.
345
Immuno!ogy Today, voI. 8, No. # !, 1987
CheIOt I ¢ t
faN:t,~s
Eosi~l)hil
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