Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse.
Production of prostaglandin E(2) (PGE(2)) is enhanced during inflammation, and this lipid mediator can dramatically modulate immune responses. There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways. To identify the EP receptors that regulate cellular immune responses, we used mouse lines in which the genes encoding each of the four EP receptors were disrupted by gene targeting. Using the mixed lymphocyte response (MLR) as a model cellular immune response, we confirmed that PGE(2) has potent antiproliferative effects on wild-type responder cells. The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE(2) in the MLR. In contrast, when responder cells lacked the EP2 receptor, PGE(2) had little effect on proliferation. Modest resistance to PGE(2) was also observed in EP4-/- responder cells. Reconstitution experiments suggest that EP2 receptors primarily inhibit the MLR through direct actions on T cells. Furthermore, PGE(2) modulates macrophage function by activating the EP4 receptor and thereby inhibiting cytokine release. Thus, PGE(2) regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions.
Nataraj
C
C
Division of Nephrology, Duke University and Durham Veterans' Affairs Medical Centers, Durham, NC 27705, USA.
Thomas
D W
DW
Tilley
S L
SL
Nguyen
M T
MT
Mannon
R
R
Koller
B H
BH
Coffman
T M
TM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D015232:Dinoprostone / Q000494:pharmacology; D015870:Gene Expression; D007111:Immunity, Cellular; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000145:classification / Q000235:genetics / Q000276:immunology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D017931:DNA Primers; D020033:Protein Isoforms; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; C545648:Ptger3 protein, mouse; C545651:Ptger4 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015232:Dinoprostone