Alternative titles; symbols
HGNC Approved Gene Symbol: CD14
Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:140,631,732-140,633,701 (from NCBI)
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).
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.
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.
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.
Tang et al. (2017) found that expression of TLR4 (603030) and its coreceptor CD14 parallels lesion burden in cerebral cavernous malformations (CCM; 116860). They studied 830 genetic variants of 56 inflammatory and immune related genes in 188 patients who carried a KRIT1 Q455X variant (604214.0004) and measured CCM lesion burden using MRI. Following statistical analysis, SNPs in only 2 genes, TLR4 (rs10759930) and CD14 (rs778587), were found to be significantly associated with increased CCM lesion number. Further analysis of genes in TLR4-MEKK3-KLF2/4 signaling pathways identified additional SNPs for TLR4 (rs10759931) and CD14 (rs778588) in linkage disequilibrium with those previously identified, but none in other pathway genes that associated with altered lesion burden. Tang et al. (2017) found that the SNPs in TLR4 and CD14 that are associated with increased CCM lesion number are in the 5-prime genomic region of each gene and constitutes cis expression quantitative trait loci (QTLs) that positively regulate whole blood cell expression of TLR4 and CD14 in a dose-dependent manner corresponding with risk allele number. These results were corroborated using the GTEx Consortium data. Additionally, global loss of Cd14 prevented CCM formation in susceptible mice with endothelial-specific deletion of Krit1 (Krit1(ECKO) mice).
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.
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.
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.
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. [PubMed: 10226067] [Full Text: https://doi.org/10.1165/ajrcmb.20.5.3494]
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. [PubMed: 21078886] [Full Text: https://doi.org/10.1084/jem.20101111]
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. [PubMed: 12214235] [Full Text: https://doi.org/10.1038/nature01023]
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. [PubMed: 9548256] [Full Text: https://doi.org/10.1038/33169]
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. [PubMed: 1694207]
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. [PubMed: 2448876] [Full Text: https://doi.org/10.1126/science.2448876]
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. [PubMed: 8798531] [Full Text: https://doi.org/10.1074/jbc.271.38.23310]
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. [PubMed: 8612135] [Full Text: https://doi.org/10.1016/s1074-7613(00)80254-x]
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. [PubMed: 10385492] [Full Text: https://doi.org/10.1161/01.cir.99.25.3218]
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. [PubMed: 23264655] [Full Text: https://doi.org/10.4049/jimmunol.1202446]
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. [PubMed: 11062499] [Full Text: https://doi.org/10.1038/80833]
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. [PubMed: 12241724] [Full Text: https://doi.org/10.1016/S0140-6736(02)09641-1]
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. [PubMed: 8516290] [Full Text: https://doi.org/10.1073/pnas.90.12.5484]
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. [PubMed: 11698458] [Full Text: https://doi.org/10.4049/jimmunol.167.10.5838]
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. [PubMed: 14517520] [Full Text: https://doi.org/10.1067/S0022-3476(03)00330-5]
Savill, J. Phagocytic docking without shocking. Nature 392: 442-443, 1998. [PubMed: 9548247] [Full Text: https://doi.org/10.1038/33025]
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. [PubMed: 2472171] [Full Text: https://doi.org/10.1016/0167-4781(80)90012-3]
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. [PubMed: 10980225] [Full Text: https://doi.org/10.1016/s0002-9149(00)01054-7]
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. [PubMed: 23636320] [Full Text: https://doi.org/10.1038/nature12118]
Tang, A. T., Choi, J. P., Kotzin, J. J., Yang, Y., Hong, C. C., Hobson, N., Girard, R., Zeineddine, H. A., Lightle, R., Moore, T., Cao, Y., Shenkar, R., and 18 others. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545: 305-310, 2017. [PubMed: 28489816] [Full Text: https://doi.org/10.1038/nature22075]
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. [PubMed: 10195920] [Full Text: https://doi.org/10.1161/01.atv.19.4.932]
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. [PubMed: 1698311] [Full Text: https://doi.org/10.1126/science.1698311]
Wright, S. D. CD14: a leukocyte membrane protein that functions in the response to endotoxin. (Abstract) FASEB J. 4: A1848 only, 1990.
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. [PubMed: 12566518] [Full Text: https://doi.org/10.1136/jmg.40.2.104]
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. [PubMed: 19525933] [Full Text: https://doi.org/10.1038/nature08118]
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. [PubMed: 22078883] [Full Text: https://doi.org/10.1016/j.cell.2011.09.051]