RBCC Red Blood Cell Collection

CD14 [Confidence: low (only semi-automatic identification from reviews)]
Monocyte differentiation antigen CD14 (Myeloid cell-specific leucine-rich glycoprotein; CD14; Monocyte differentiation antigen CD14, urinary form; Monocyte differentiation antigen CD14, membrane-bound form; Flags: Precursor)

UniProt P08571
ID CD14_HUMAN Reviewed; 375 AA.
AC P08571; Q53XT5; Q96FR6; Q96L99; Q9UNS3;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-MAR-2002, sequence version 2.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Monocyte differentiation antigen CD14;
DE AltName: Full=Myeloid cell-specific leucine-rich glycoprotein;
DE AltName: CD_antigen=CD14;
DE Contains:
DE RecName: Full=Monocyte differentiation antigen CD14, urinary form;
DE Contains:
DE RecName: Full=Monocyte differentiation antigen CD14, membrane-bound form;
DE Flags: Precursor;
GN Name=CD14;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3385210;
RA Haziot A., Chen S., Ferrero E., Low M.G., Silber R., Goyert S.M.;
RT "The monocyte differentiation antigen, CD14, is anchored to the cell
RT membrane by a phosphatidylinositol linkage.";
RL J. Immunol. 141:547-552(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Lymphocyte;
RX PubMed=2453848; DOI=10.1093/nar/16.9.4173;
RA Ferrero E., Goyert S.M.;
RT "Nucleotide sequence of the gene encoding the monocyte differentiation
RT antigen, CD14.";
RL Nucleic Acids Res. 16:4173-4173(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Macrophage;
RX PubMed=2472171; DOI=10.1016/0167-4781(80)90012-3;
RA Setoguchi M., Nasu N., Yoshida S., Higuchi Y., Akizuki S.,
RA Yamamoto S.;
RT "Mouse and human CD14 (myeloid cell-specific leucine-rich
RT glycoprotein) primary structure deduced from cDNA clones.";
RL Biochim. Biophys. Acta 1008:213-222(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2462937;
RA Simmons D.L., Tan S., Tenen D.G., Nicholson-Weller A., Seed B.;
RT "Monocyte antigen CD14 is a phospholipid anchored membrane protein.";
RL Blood 73:284-289(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Promyelocytic leukemia;
RA Long J.Y., Xue Y.N., Sun L., Wang H.X.;
RT "Cloning and sequencing of human CD14 gene.";
RL Sheng Wu Hua Xue Yu Sheng Wu Wu Li Jin Zhan 25:377-378(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=18810425; DOI=10.1007/s00251-008-0332-0;
RA Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T.,
RA Kimura A.;
RT "Natural selection in the TLR-related genes in the course of primate
RT evolution.";
RL Immunogenetics 60:727-735(2008).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-125.
RC TISSUE=Glioblastoma;
RA Deininger M.H., Meyermann R., Schluesener H.J.;
RT "Expression and secretion of CD14 in glial neoplasms of the brain.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP PROTEIN SEQUENCE OF 362-367.
RX PubMed=2779588; DOI=10.1016/0161-5890(89)90048-5;
RA Bazil V., Baudys M., Hilgert I., Stefanova I., Low M.G., Zbrozek J.,
RA Horejsi V.;
RT "Structural relationship between the soluble and membrane-bound forms
RT of human monocyte surface glycoprotein CD14.";
RL Mol. Immunol. 26:657-662(1989).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-151 AND ASN-282, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-323, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-336, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (4.0 ANGSTROMS) OF 26-335, DISULFIDE BONDS, AND
RP FUNCTION.
RX PubMed=23264655; DOI=10.4049/jimmunol.1202446;
RA Kelley S.L., Lukk T., Nair S.K., Tapping R.I.;
RT "The crystal structure of human soluble CD14 reveals a bent solenoid
RT with a hydrophobic amino-terminal pocket.";
RL J. Immunol. 190:1304-1311(2013).
CC -!- FUNCTION: In concert with LBP, binds to monomeric
CC lipopolysaccharide and delivers it to the MD-2/TLR4 complex,
CC thereby mediating the innate immune response to bacterial
CC lipopolysaccharide (LPS). Acts via MyD88, TIRAP and TRAF6, leading
CC to NF-kappa-B activation, cytokine secretion and the inflammatory
CC response. Up-regulates cell surface molecules, including adhesion
CC molecules.
CC -!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a
CC multi-protein complex containing at least CD14, MD-2 and TLR4.
CC -!- INTERACTION:
CC Q12841:FSTL1; NbExp=3; IntAct=EBI-3905196, EBI-2349801;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor.
CC -!- TISSUE SPECIFICITY: Expressed strongly on the surface of monocytes
CC and weakly on the surface of granulocytes; also expressed by most
CC tissue macrophages.
CC -!- PTM: N- and O- glycosylated. O-glycosylated with a core 1 or
CC possibly core 8 glycan.
CC -!- SIMILARITY: Contains 11 LRR (leucine-rich) repeats.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CD14 entry;
CC URL="http://en.wikipedia.org/wiki/CD14";
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DR EMBL; X06882; CAA29999.1; -; Genomic_DNA.
DR EMBL; X13334; CAA31711.1; -; mRNA.
DR EMBL; M86511; AAA51930.1; -; mRNA.
DR EMBL; AF097942; AAC83816.1; -; mRNA.
DR EMBL; AB446505; BAG55282.1; -; mRNA.
DR EMBL; BT007331; AAP35995.1; -; mRNA.
DR EMBL; CH471062; EAW62037.1; -; Genomic_DNA.
DR EMBL; BC010507; AAH10507.1; -; mRNA.
DR EMBL; AY044269; AAL02401.1; -; mRNA.
DR PIR; A27637; TDHUM4.
DR RefSeq; NP_000582.1; NM_000591.3.
DR RefSeq; NP_001035110.1; NM_001040021.2.
DR RefSeq; NP_001167575.1; NM_001174104.1.
DR RefSeq; NP_001167576.1; NM_001174105.1.
DR UniGene; Hs.163867; -.
DR PDB; 4GLP; X-ray; 4.00 A; A=26-335.
DR PDBsum; 4GLP; -.
DR ProteinModelPortal; P08571; -.
DR SMR; P08571; 26-335.
DR DIP; DIP-1030N; -.
DR IntAct; P08571; 8.
DR MINT; MINT-7990664; -.
DR STRING; 9606.ENSP00000304236; -.
DR PhosphoSite; P08571; -.
DR DMDM; 20141203; -.
DR PaxDb; P08571; -.
DR PeptideAtlas; P08571; -.
DR PRIDE; P08571; -.
DR DNASU; 929; -.
DR Ensembl; ENST00000302014; ENSP00000304236; ENSG00000170458.
DR Ensembl; ENST00000401743; ENSP00000385519; ENSG00000170458.
DR GeneID; 929; -.
DR KEGG; hsa:929; -.
DR UCSC; uc003lgi.2; human.
DR CTD; 929; -.
DR GeneCards; GC05M139991; -.
DR HGNC; HGNC:1628; CD14.
DR HPA; HPA001887; -.
DR HPA; HPA002127; -.
DR MIM; 158120; gene.
DR neXtProt; NX_P08571; -.
DR PharmGKB; PA26188; -.
DR eggNOG; NOG86091; -.
DR HOGENOM; HOG000237268; -.
DR HOVERGEN; HBG005269; -.
DR InParanoid; P08571; -.
DR KO; K04391; -.
DR OMA; LCPHKFP; -.
DR OrthoDB; EOG751NFQ; -.
DR PhylomeDB; P08571; -.
DR Reactome; REACT_6900; Immune System.
DR GeneWiki; CD14; -.
DR GenomeRNAi; 929; -.
DR NextBio; 3850; -.
DR PMAP-CutDB; P08571; -.
DR PRO; PR:P08571; -.
DR ArrayExpress; P08571; -.
DR Bgee; P08571; -.
DR CleanEx; HS_CD14; -.
DR Genevestigator; P08571; -.
DR GO; GO:0031225; C:anchored to membrane; IEA:UniProtKB-KW.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0001530; F:lipopolysaccharide binding; IDA:MGI.
DR GO; GO:0070891; F:lipoteichoic acid binding; IDA:MGI.
DR GO; GO:0001847; F:opsonin receptor activity; TAS:BHF-UCL.
DR GO; GO:0016019; F:peptidoglycan receptor activity; TAS:ProtInc.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:MGI.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IDA:MGI.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006909; P:phagocytosis; TAS:ProtInc.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IEA:Ensembl.
DR GO; GO:0045807; P:positive regulation of endocytosis; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:MGI.
DR GO; GO:0009408; P:response to heat; IEA:Ensembl.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR016337; Monocyte_diff_Ag_CD14.
DR Pfam; PF00560; LRR_1; 1.
DR PIRSF; PIRSF002017; CD14; 1.
DR PROSITE; PS51450; LRR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; GPI-anchor;
KW Immunity; Inflammatory response; Innate immunity; Leucine-rich repeat;
KW Lipoprotein; Membrane; Polymorphism; Reference proteome; Repeat;
KW Signal.
FT SIGNAL 1 19
FT CHAIN 20 367 Monocyte differentiation antigen CD14,
FT urinary form.
FT /FTId=PRO_0000020884.
FT CHAIN 20 345 Monocyte differentiation antigen CD14,
FT membrane-bound form.
FT /FTId=PRO_0000020885.
FT PROPEP 346 375 Removed in mature form (Potential).
FT /FTId=PRO_0000020886.
FT REPEAT 54 82 LRR 1.
FT REPEAT 83 118 LRR 2.
FT REPEAT 119 144 LRR 3.
FT REPEAT 145 172 LRR 4.
FT REPEAT 173 196 LRR 5.
FT REPEAT 197 224 LRR 6.
FT REPEAT 225 251 LRR 7.
FT REPEAT 252 278 LRR 8.
FT REPEAT 279 299 LRR 9.
FT REPEAT 300 321 LRR 10.
FT REPEAT 322 349 LRR 11.
FT REGION 42 89 Ligand-binding pocket rim.
FT LIPID 345 345 GPI-anchor amidated asparagine
FT (Potential).
FT CARBOHYD 37 37 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 151 151 N-linked (GlcNAc...).
FT CARBOHYD 282 282 N-linked (GlcNAc...).
FT CARBOHYD 323 323 N-linked (GlcNAc...).
FT CARBOHYD 336 336 O-linked (GalNAc...).
FT DISULFID 25 36
FT DISULFID 34 51
FT DISULFID 187 217
FT DISULFID 241 272
FT VARIANT 204 204 N -> D (in dbSNP:rs2228049).
FT /FTId=VAR_024302.
FT VARIANT 341 341 E -> K (in dbSNP:rs11556179).
FT /FTId=VAR_050771.
FT CONFLICT 187 187 C -> Y (in Ref. 2; CAA29999).
FT CONFLICT 303 303 D -> E (in Ref. 5; AAC83816).
SQ SEQUENCE 375 AA; 40076 MW; 1746CDB41F394F8D CRC64;
MERASCLLLL LLPLVHVSAT TPEPCELDDE DFRCVCNFSE PQPDWSEAFQ CVSAVEVEIH
AGGLNLEPFL KRVDADADPR QYADTVKALR VRRLTVGAAQ VPAQLLVGAL RVLAYSRLKE
LTLEDLKITG TMPPLPLEAT GLALSSLRLR NVSWATGRSW LAELQQWLKP GLKVLSIAQA
HSPAFSCEQV RAFPALTSLD LSDNPGLGER GLMAALCPHK FPAIQNLALR NTGMETPTGV
CAALAAAGVQ PHSLDLSHNS LRATVNPSAP RCMWSSALNS LNLSFAGLEQ VPKGLPAKLR
VLDLSCNRLN RAPQPDELPE VDNLTLDGNP FLVPGTALPH EGSMNSGVVP ACARSTLSVG
VSGTLVLLQG ARGFA
//

MIM 158120
*RECORD*
*FIELD* NO
158120
*FIELD* TI
*158120 MONOCYTE DIFFERENTIATION ANTIGEN CD14; CD14
;;MYELOID CELL-SPECIFIC LEUCINE-RICH GLYCOPROTEIN
read more*FIELD* TX

DESCRIPTION

CD14 is a single-copy gene encoding 2 protein forms: a 50- to 55-kD
glycosylphosphatidylinositol-anchored membrane protein (mCD14) and a
monocyte or liver-derived soluble serum protein (sCD14) that lacks the
anchor. Both molecules are critical for lipopolysaccharide
(LPS)-dependent signal transduction, and sCD14 confers LPS sensitivity
to cells lacking mCD14. Increased sCD14 levels are associated with
inflammatory infectious diseases and high mortality in gram-negative
shock (LeVan et al., 2001).

CLONING

Differentiation of myelomonocytic cells from pluripotent stem cells to
mature functioning monocytes/macrophages and granulocytes is accompanied
by a variety of changes, including the expression of new cell surface
antigens. One of these antigens, CD14, a 55-kD glycoprotein, is
preferentially expressed on the surface of mature cells of the monocytic
lineage. Goyert et al. (1988) isolated a cDNA clone encoding CD14 and
isolated the CD14 gene.

Ferrero et al. (1990) demonstrated that, as in man, the expression of
murine CD14 is limited to the myeloid lineage. In both mouse and man,
the CD14 protein contains leucine-rich motif that is repeated 10 times.

BIOCHEMICAL FEATURES

Kelley et al. (2013) determined the crystal structure of human CD14 at
4-angstrom resolution. The structure revealed a bent solenoid typical of
leucine-rich repeat proteins with an N-terminal pocket that likely binds
acylated ligands, such as LPS. The structures of human and mouse CD14
are similar, except that human CD14 contains an expanded pocket and
alternative rim residues that are probably important for LPS binding and
cell activation.

GENE FUNCTION

The expression profile of CD14, as well as its inclusion in the family
of leucine-rich proteins and the chromosomal location of other receptor
genes, supports the hypothesis that CD14 functions as a receptor. Its
receptor function was indeed demonstrated by Wright (1990) who showed
that it is a receptor for the lipopolysaccharide-binding
protein:lipopolysaccharide complex (LBP; 151990:LPS); also see Wright et
al. (1990). Gupta et al. (1996) transfected mouse 70Z/3 cells with human
CD14 and showed that these cells were responsive to peptidoglycan (PGN),
a polymer of alternating GlcNAc and MurNAc cross-linked by short
peptides, that is present in the cell walls of all bacteria, but is
particularly abundant in gram-positive bacteria. They concluded that
CD14 serves as a cell-activating receptor not only for LPS but also for
PGN.

Cells undergoing programmed cell death (apoptosis) are cleared rapidly
in vivo by phagocytes without inducing inflammation. Devitt et al.
(1998) showed that the glycoprotein CD14 on the surface of human
macrophages is important for the recognition and clearance of apoptotic
cells. CD14 can also act as a receptor that binds bacterial LPS,
triggering inflammatory responses. Overstimulation of CD14 by LPS can
cause the often fatal toxic-shock syndrome. Devitt et al. (1998) showed
that apoptotic cells interact with CD14, triggering phagocytosis of the
apoptotic cells. This interaction depends on a region of CD14 that is
identical to, or at least closely associated with, a region known to
bind LPS. However, apoptotic cells, unlike LPS, do not provoke the
release of proinflammatory cytokines from macrophages. These results
indicated that clearance of apoptotic cells is mediated by a receptor
whose interactions with 'nonself' components (LPS) and 'self' components
(apoptotic cells) produce distinct macrophage responses.

Savill (1998) summarized understanding of how ced-5 (see DOCK1; 601403)
and CD14 together with other molecules function in the engulfment of
cell corpses by macrophages in the process of programmed cell death. The
model incorporated the newly proposed functions of ced-5 and CD14.

LPS interacts with LBP and CD14 to present LPS to TLR4 (603030), which
activates inflammatory gene expression through NF-kappa-B (see 164011)
and MAPK signaling. Bochkov et al. (2002) demonstrated that oxidized
phospholipids inhibit LPS-induced but not TNF-alpha (191160)-induced or
interleukin-1-beta (147720)-induced NF-kappa-B-mediated upregulation of
inflammatory genes, by blocking the interaction of LPS with LBP and
CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited
inflammation and protected mice from lethal endotoxin shock. Thus, in
severe gram-negative bacterial infection, endogenously formed oxidized
phospholipids may function as a negative feedback to blunt innate immune
responses. Furthermore, Bochkov et al. (2002) identified chemical
structures capable of inhibiting the effects of endotoxins such as LPS
that could be used for the development of new drugs for treatment of
sepsis.

Children of farmers are at decreased risk of developing allergies.
Results of epidemiologic studies suggested that increased exposure to
microbial compounds might be responsible for this reduced risk.
Alterations in adaptive immune response were thought to be the
underlying mechanism. Lauener et al. (2002) measured the expression of
receptors for microbial compounds known to trigger the innate immune
response. They showed that blood cells from farmers' children expressed
significantly higher amounts of CD14 and Toll-like receptor-2 (TLR2;
603028) than those from non-farmers' children. They proposed that the
innate immune system responds to the microbial burden in the environment
and modulates the development of allergic disease.

Zanoni et al. (2009) found that stimulation of murine bone
marrow-derived dendritic cells (DCs) with LPS induced Src (190090)
kinase and Plcg2 (600220) activation, Ca(2+) influx, and calcineurin
(see 114105)-dependent nuclear Nfat (see 600490) translocation.
Induction of this pathway was Tlr4 independent and entirely dependent on
Cd14. Nfat activation was necessary for apoptotic death of terminally
differentiated DCs, allowing for maintenance of self-tolerance and
prevention of autoimmunity. Blocking this pathway in vivo resulted in
prolonged DC survival and an increase in T-cell priming capability.
Zanoni et al. (2009) concluded that CD14 is involved, through NFAT
activation, in regulation of the DC life cycle.

By coimmunoprecipitation and confocal microscopic analysis, Baumann et
al. (2010) showed that CD14 interacted with TLR7 (300365) and TLR9
(605474) in mouse and human cells and was required for TLR7- and
TLR9-dependent induction of proinflammatory cytokines. Cd14 was required
for Tlr9-dependent immune responses in mice and for optimal nucleic acid
uptake in mouse macrophages. Cd14 was dispensable for viral uptake in
mice, but it was required for triggering of TLR-dependent cytokine
responses. Baumann et al. (2010) concluded that CD14 has a dual role in
nucleic acid-mediated TLR activation by promoting selective uptake of
nucleic acids and acting as a coreceptor for endosomal TLR activation.

Using flow cytometry and confocal microscopy in mouse cells, Zanoni et
al. (2011) demonstrated that Cd14 chaperoned LPS to Tlr4, leading to Syk
(600085)-dependent internalization of Tlr4 and signaling through Trif
(607601). Zanoni et al. (2011) concluded that pathogen recognition
receptors induce both membrane transport and signal transduction.

Shirey et al. (2013) reported that CD14 and TLR2 are required for
protection against influenza-induced lethality in mice mediated by
Eritoran (also known as E5564), a potent, well-tolerated, synthetic TLR4
antagonist. Therapeutic administration of Eritoran blocked
influenza-induced lethality in mice, as well as lung pathology, clinical
symptoms, cytokine and oxidized phospholipid expression, and decreased
viral titers. CD14 directly binds Eritoran and inhibits ligand binding
to MD2 (605243). Shirey et al. (2013) concluded that Eritoran blockade
of TLR signaling represents a novel therapeutic approach for
inflammation associated with influenza, and possibly other infections.

MAPPING

Goyert et al. (1988) demonstrated by in situ hybridization and study of
somatic cell hybrid DNA that the gene is located at bands 5q23-q31.
Thus, CD14 is located in a region of chromosome 5 that contains a
cluster of genes that encode several myeloid-specific growth factors
(IL3; 147740) and granulocyte-macrophage colony-stimulating factor
(CSF2; 138960) or growth factor receptors (FMS receptor for CFS1;
164770), as well as other growth factor and receptor genes
(platelet-derived growth factor receptor, 173410, beta-2-adrenergic
receptor, 109690, and endothelial cell growth factor, 131220). This is a
region that is deleted in patients with certain forms of myeloid
leukemia.

Ferrero et al. (1990) mapped the CD14 gene to mouse chromosome 18.

By fluorescence in situ hybridization studies of deleted chromosome 5
homologs in a series of 135 patients with malignant myeloid diseases, Le
Beau et al. (1993) mapped the CD14 gene and neighboring genes to 5q31.

MOLECULAR GENETICS

Baldini et al. (1999) identified a single nucleotide polymorphism (SNP)
in the proximal CD14 promoter at position -159 from the transcription
start site, resulting in a C-to-T transition. TT homozygotes had
significantly higher levels of sCD14 than did either CC or CT genotype
carriers, and they also had lower levels of IgE. Unkelbach et al.
(1999), Hubacek et al. (1999), and Shimada et al. (2000) reported an
increased risk of myocardial infarction in individuals carrying the T
allele. (Shimada et al. (2000) and Hubacek et al. (1999) reported the
C/T polymorphism as occurring at position -260 from the translation
start site.)

Some patients with Kawasaki disease (KD), an acute febrile vasculitis of
childhood, develop coronary artery lesions after the acute phase.
Nishimura et al. (2003) found no difference in genomic and allele
frequencies of the T allele at the CD14/-159 promoter region in 67
patients with KD compared to controls. However, the KD patients with TT
genotypes had more coronary artery complications than those with CT or
CC genotypes, and the frequency of the T allele was significantly higher
than that of the C allele in KD patients. Nishimura et al. (2003)
concluded that the T allele and the TT genotype are risk factors for the
coronary artery complications in patients with KD, implicating a
possible relationship to the magnitude of the CD14 toll-like receptor
response.

Using EMSA analysis, LeVan et al. (2001) showed that the T allele at
position -159 in the proximal CD14 promoter has a decreased affinity for
DNA/protein interactions at a GC box containing a binding site for SP1
(189906), SP2 (601801), and SP3 (601804) transcription factors. Reporter
analysis demonstrated that monocytic cells with low levels of SP3, which
inhibits activating by SP1 and SP2, have increased transcriptional
activity of the T allele. In contrast, both the C and T alleles are
transcribed equivalently in SP3-rich hepatocytes. LeVan et al. (2001)
proposed that the interplay between CD14 promoter affinity and the
SP3:SP1-plus-SP2 ratio plays a critical mechanistic role in regulating
CD14 transcription and in determining the differential activity of the 2
variants of the CD14 promoter.

In a study of 216 Korean patients with IgA nephropathy (161950) who were
followed for 86 months, Yoon et al. (2003) found that an excess of the
-159C genotype occurred in patients with progressive disease (p = 0.03)
and the risk of disease progression increased as the number of C alleles
increased (p for trend = 0.002). The hazard ratio for progression in
patients with the CC genotype was 3.2 (p = 0.025) compared to patients
with the TT genotype. After lipopolysaccharide stimulation, soluble CD14
was released more abundantly from the peripheral blood mononuclear cells
of TT patients than from those of CC patients (p = 0.006), although
there was no difference in membrane-bound CD14 expression. TT patients
released less IL6 (147620) than CC patients after stimulation (p =
0.0003). Yoon et al. (2003) suggested that the CD14 -159 polymorphism is
an important marker for the progression of IgA nephropathy and may
modulate the level of the inflammatory response.

ANIMAL MODEL

Haziot et al. (1996) reported that Cd14-deficient mice were resistant to
LPS-induced shock.

Kurt-Jones et al. (2000) determined that proinflammatory cytokine
responses to respiratory syncytial virus (RSV) F protein were absent or
diminished in mice with deletions of either Cd14 or Tlr4 (603030),
respectively. Importantly, Tlr4 -/- mice had higher levels of infectious
virus in their lungs and were either unable to clear the virus or
cleared the virus several days later than wildtype mice. The authors
concluded that TLR4 and CD14 appear to be important not only in
recognizing bacterial structures such as lipopolysaccharide, but are
important in innate immune responses to viruses as well.

*FIELD* SA
Setoguchi et al. (1989)
*FIELD* RF
1. Baldini, M.; Lohman, I. C.; Halonen, M.; Erickson, R. P.; Holt,
P. G.; Martinez, F. D.: A polymorphism in the 5-prime flanking region
of the CD14 gene is associated with circulating soluble CD14 levels
and with total serum immunoglobulin E. Am. J. Resp. Cell Molec. Biol. 20:
976-983, 1999.

2. Baumann, C. L.; Aspalter, I. M.; Sharif, O.; Pichlmair, A.; Bluml,
S.; Grebien, F.; Bruckner, M.; Pasierbek, P.; Aumayr, K.; Planyavsky,
M.; Bennett, K. L.; Colinge, J.; Knapp, S.; Superti-Furga, G.: CD14
is a coreceptor of Toll-like receptors 7 and 9. J. Exp. Med. 207:
2689-2701, 2010.

3. Bochkov, V. N.; Kadl, A.; Huber, J.; Gruber, F.; Binder, B. R.;
Leitinger, N.: Protective role of phospholipid oxidation products
in endotoxin-induced tissue damage. Nature 419: 77-81, 2002.

4. Devitt, A.; Moffatt, O. D.; Raykundalia, C.; Capra, J. D.; Simmons,
D. L.; Gregory, C. D.: Human CD14 mediates recognition and phagocytosis
of apoptotic cells. Nature 392: 505-509, 1998.

5. Ferrero, E.; Hsieh, C.-L.; Francke, U.; Goyert, S. M.: CD14 is
a member of the family of leucine-rich proteins and is encoded by
a gene syntenic with multiple receptor genes. J. Immun. 145: 331-336,
1990.

6. Goyert, S. M.; Ferrero, E.; Rettig, W. J.; Yenamandra, A. K.; Obata,
F.; Le Beau, M. M.: The CD14 monocyte differentiation antigen maps
to a region encoding growth factors and receptors. Science 239:
497-500, 1988.

7. Gupta, D.; Kirkland, T. N.; Viriyakosol, S.; Dziarski, R.: CD14
is a cell-activating receptor for bacterial peptidoglycan. J. Biol.
Chem. 271: 23310-23316, 1996.

8. Haziot, A.; Ferrero, E.; Kontgen, F.; Hijiya, N.; Yamamoto, S.;
Silver, J.; Stewart, C. L.; Goyert, S. M.: Resistance to endotoxin
shock and reduced dissemination of gram-negative bacteria in CD14-deficient
mice. Immunity 4: 407-414, 1996.

9. Hubacek, J. A.; Rothe, G.; Pit'ha, J.; Skodova, Z.; Stanek, V.;
Poledne, R.; Schmitz, G.: C(-260)-to-T polymorphism in the promoter
of the CD14 monocyte receptor gene as a risk factor for myocardial
infarction. Circulation 99: 3218-3220, 1999. Note: Erratum: Circulation
100: 2550 only, 1999.

10. Kelley, S. L.; Lukk, T.; Nair, S. K.; Tapping, R. I.: The crystal
structure of human soluble CD14 reveals a bent solenoid with a hydrophobic
amino-terminal pocket. J. Immun. 190: 1304-1311, 2013.

11. Kurt-Jones, E. A.; Popova, L.; Kwinn, L.; Haynes, L. M.; Jones,
L. P.; Tripp, R. A.; Walsh, E. E.; Freeman, M. W.; Golenbock, D. T.;
Anderson, L. J.; Finberg, R. W.: Pattern recognition receptors TLR4
and CD14 mediate response to respiratory syncytial virus. Nature
Immun. 1: 398-401, 2000.

12. Lauener, R. P.; Birchler, T.; Adamski, J.; Braun-Fahrlander, C.;
Bufe, A.; Herz, U.; von Mutius, E.; Nowak, D.; Riedler, J.; Waser,
M.; Sennhauser, F. H.; ALEX study group: Expression of CD14 and
Toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360:
465-466, 2002.

13. Le Beau, M. M.; Espinosa, R., III; Neuman, W. L.; Stock, W.; Roulston,
D.; Larson, R. A.; Keinanen, M.; Westbrook, C. A.: Cytogenetic and
molecular delineation of the smallest commonly deleted region of chromosome
5 in malignant myeloid diseases. Proc. Nat. Acad. Sci. 90: 5484-5488,
1993.

14. LeVan, T. D.; Bloom, J. W.; Bailey, T. J.; Karp, C. L.; Halonen,
M.; Martinez, F. D.; Vercelli, D.: A common single nucleotide polymorphism
in the CD14 promoter decreases the affinity of Sp protein binding
and enhances transcriptional activity. J. Immun. 167: 5838-5844,
2001.

15. Nishimura, S.; Zaitsu, M.; Hara, M.; Yokota, G.; Watanabe, M.;
Ueda, Y.; Imayoshi, M.; Ishii, E.; Tasaki, H.; Hamasaki, Y.: A polymorphism
in the promoter of the CD14 gene (CD14/-159) is associated with the
development of coronary artery lesions in patients with Kawasaki disease. J.
Pediat. 143: 357-362, 2003.

16. Savill, J.: Phagocytic docking without shocking. Nature 392:
442-443, 1998.

17. Setoguchi, M.; Nasu, N.; Yoshida, S.; Higuchi, Y.; Akizuki, S.;
Yamamoto, S.: Mouse and human CD14 (myeloid cell-specific leucine-rich
glycoprotein) primary structure deduced from cDNA clones. Biochim.
Biophys. Acta 1008: 213-222, 1989.

18. Shimada, K.; Watanabe, Y.; Mokuno, H.; Iwama, Y.; Daida, H.; Yamaguchi,
H.: Common polymorphism in the promoter of the CD14 monocyte receptor
gene is associated with acute myocardial infarction in Japanese men. Am.
J. Cardiol. 86: 682-684, 2000.

19. Shirey, K. A.; Lai, W.; Scott, A. J.; Lipsky, M.; Mistry, P.;
Pletneva, L. M.; Karp, C. L.; McAlees, J.; Gioannini, T. L.; Weiss,
J.; Chen, W. H.; Ernst, R. K.; Rossignol, D. P.; Gusovsky, F.; Blanco,
J. C. G.; Vogel, S. N.: The TLR4 antagonist Eritoran protects mice
from lethal influenza infection. Nature 497: 498-502, 2013.

20. Unkelbach, K.; Gardemann, A.; Kostrzewa, M.; Philipp, M.; Tillmanns,
H.; Haberbosch, W.: A new promoter polymorphism in the gene of lipopolysaccharide
receptor CD14 is associated with expired myocardial infarction in
patients with low atherosclerotic risk profile. Arterioscler. Thromb.
Vasc. Biol. 19: 932-938, 1999.

21. Wright, S. D.: CD14: a leukocyte membrane protein that functions
in the response to endotoxin. (Abstract) FASEB J. 4: A1848 only,
1990.

22. Wright, S. D.; Ramos, R. A.; Tobias, P. S.; Ulevitch, R. J.; Mathison,
J. C.: CD14, a receptor for complexes of lipopolysaccharide (LPS)
and LPS binding protein. Science 249: 1431-1433, 1990.

23. Yoon, H.-J.; Shin, J. H.; Yang, S. H.; Chae, D.-W.; Kim, H.; Lee,
D.-S.; Kim, H. L.; Kim, S.; Lee, J. S.: Association of the CD14 gene
-159C polymorphism with progression of IgA nephropathy. J. Med. Genet. 40:
104-108, 2003.

24. Zanoni, I.; Ostuni, R.; Capuano, G.; Collini, M.; Caccia, M.;
Ronchi, A. E.; Rocchetti, M.; Mingozzi, F.; Foti, M.; Chirico, G.;
Costa, B.; Zaza, A.; Ricciardi-Castagnoli, P.; Granucci, F.: CD14
regulates the dendritic cell life cycle after LPS exposure through
NFAT activation. Nature 460: 264-268, 2009.

25. Zanoni, I.; Ostuni, R.; Marek, L. R.; Barresi, S.; Barbalat, R.;
Barton, G. M.; Granucci, F.; Kagan, J. C.: CD14 controls the LPS-induced
endocytosis of Toll-like receptor 4. Cell 147: 868-880, 2011.

*FIELD* CN
Paul J. Converse - updated: 11/6/2013
Ada Hamosh - updated: 7/11/2013
Paul J. Converse - updated: 10/26/2012
Paul J. Converse - updated: 4/29/2011
Paul J. Converse - updated: 7/16/2009
Marla J. F. O'Neill - updated: 12/28/2004
Natalie E. Krasikov - updated: 3/12/2004
Victor A. McKusick - updated: 10/15/2002
Ada Hamosh - updated: 9/11/2002
Paul J. Converse - updated: 2/15/2002
Paul J. Converse - updated: 11/21/2000
Victor A. McKusick - updated: 9/9/1998

*FIELD* CD
Victor A. McKusick: 7/9/1987

*FIELD* ED
mgross: 11/11/2013
mcolton: 11/7/2013
mcolton: 11/6/2013
alopez: 7/11/2013
mgross: 11/19/2012
terry: 10/26/2012
terry: 8/31/2012
mgross: 5/11/2011
terry: 4/29/2011
mgross: 7/16/2009
terry: 7/16/2009
alopez: 12/6/2006
carol: 12/28/2004
carol: 3/17/2004
terry: 3/12/2004
terry: 1/2/2003
cwells: 10/22/2002
terry: 10/15/2002
alopez: 9/12/2002
cwells: 9/11/2002
mgross: 2/15/2002
mgross: 11/21/2000
alopez: 9/10/1998
terry: 9/9/1998
jenny: 3/7/1997
warfield: 3/3/1994
carol: 7/1/1993
supermim: 3/16/1992
carol: 12/4/1991
carol: 10/24/1990
carol: 10/1/1990