Role Of CD14 Research Articles

Role of CD14 in human disease.

The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses to pathogens and tissue injury in macrophages and monocytes. However, roles for CD14 are increasingly being uncovered in disease responses in epithelial and endothelial cells. Consistent with these broader functions, CD14 expression is altered in a variety of non-immune cell types in response to a several of disease states. Moreover, soluble CD14 activated by factors from both pathogens and tissue damage may initiate signalling in a variety of non-immune cells. This review examined the current understanding CD14 in innate immunity as well as its potential functions in nonimmune cells and associated human diseases.

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

ObjectivesTo define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).MethodsRNA-sequencing was performed on CD4+, CD8+, CD14+ and CD19+ cells sorted from pretreatment...

Clinical Significance of Serum CD14 and Its Polymorphism as a Biomarker of Non-Alcoholic Fatty Liver Disease

Background: Liver inflammation is deliberated a risk factor for the ongoing liver damage including non-alcoholic steatohepatitis, cirrhosis, and hepatoma. CD14, an effectual mediator for the monocytes activation, has been postulated as a marker of liver inflammation and fibrosis. This study is constructed to detect the alterations in the CD14 serum levels in 40 NAFLD cases and 14 healthy controls along with to analyze the role of CD14 polymorphisms in the causation and severity of Non-Alcoholic Fatty Liver Disease (NAFLD). Liver enzymes, glycated hemoglobin, together with lipid profile were estimated in all included subjects. The diagnosis of NAFLD depends largely on ultrasonography. NAFLD fibrosis score and FIB-4 score were calculated. Serum CD14 was quantified by EnzymeLinked Immunosorbent Assay (ELISA) and C14-159C/T SNP was genotyped via Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphisms (RFLP). Results: Serum CD14 was markedly higher in the diabetic subjects either lean or overweight/obese than the controls (P<0.05). Receiver Operating Characteristic (ROC) curve showed that the optimum cutoff for CD14 was 2.97 ng/ml for discriminating NAFLD patients from their healthy counterparts with a sensitivity of 76.3% and specificity of 78.6%. There was no discrepancy in the prevalence of CD14 genotypes among NAFLD cases and controls. Moreover, the frequency of the CD14 genotypes was analogous in NAFLD patients with NFS≤0.676 and patients with NFS>0.676 (P=1.000). Conclusion: The former observations advocate the potential role of CD14 in both the pathogenesis and progression of NAFLD. Yet, it didn't correlate with the NFS, consequently it couldn't forecast the severity of the disease. Furthermore, no association was distinguished linking CD14 C-(159) T polymorphism and the risk of NAFLD occurrence.

Vernal keratoconjunctivitis activity induces decrease of ocular surface CD14, TLR-4 and TLR-9 expression.

CD14 is involved in the modulation of immune reaction via toll-like receptors (TLR) and may influence the development of allergic diseases. The role of CD14 in vernal keratoconjunctivitis (VKC) has not yet been investigated. The aim of this study is to evaluate changes of tear soluble sCD14 and conjunctival CD14, TLR-4 and 9 expression in patients with VKC in the active and quiescent phases. Eighteen patients with VKC during active inflammation (group A, N = 9), in the quiescent phase (group Q, N = 5) and after recovery (group R, N = 4) and 10 healthy subjects were included. Expression of sCD14 in tears and of CD14, TLR-4, and TLR-9 by conjunctival epithelium were evaluated by Western Blot in all groups. Expression of tear sCD14 and of conjunctival CD14, TLR-4, and TLR-9 was significantly decreased in group A when compared with healthy subjects and with VKC group Q and R. Lower expression of sCD14, CD14, TLR-4, and TLR-9 were significantly correlated with the severity of papillary reaction, while the lower sCD14 was correlated with severity of conjunctival hyperemia. Tear sCD14, and conjunctival CD14, TLR4, and TLR-9 decreased during ocular surface inflammatory reaction in patients with VKC. CD14 and TLRs ocular surface evaluation may represent biomarkers of VKC activity and novel therapeutic target.

Linking periodontitis and adverse pregnancy outcomes through CD14+ CD16+ monocytes

One of the prevalent medical issues that deserve global attention is adverse pregnancy outcomes and preterm low birth weight deliveries which have a significant impact on neonatal health. Periodontitis has been implicated as a significant risk factor for adverse effects in pregnancy. Elevated levels of periodontal pathogenic bacteria and proinflammatory cytokines which are pathognomonic features of periodontitis are believed to cause placental infection and premature rupture of the amniotic membrane consequently leading to preterm delivery. The role of CD14+CD16+ monocytes as a causal link between periodontitis and adverse pregnancy outcomes has not been researched so far, although an elevation of these cells has been independently demonstrated in both conditions. With the available background information, this hypothesis attempts to derive a mechanistic link between periodontitis and adverse pregnancy outcomes through the participation of CD14+CD16+ monocytes.

Increased both PD\u2013L1 and PD\u2013L2 expressions on monocytes of patients with hepatocellular carcinoma was associated with a poor prognosis

Anti-programmed cell death-1 (PD-1) antibodies has been approved to treat HCC. Some PD-1 ligands (PD–L1 and PD–L2) negative tumors respond to treatment of anti-PD-1 antibodies, and this fact may be caused by the expression of PD-1 ligands on non-tumor cells. PD–L1 was recently found to be expressed on CD14+ cells from cancer patients. We investigate PD-1 ligands expression on CD14+ cells of patients with HCC and the role of CD14+ cells in an antitumor response. In this study, 87 patients diagnosed with HCC were enrolled. CD14+ cells from patients with HCC expressed PD–L1 (4.5–95.5%) and PD–L2 (0.2–95.0%). According to cut-off values, we classified patients as those either with PD–L1+PD–L2+CD14+ cells or other types of CD14+ cells. The overall survival of patients with PD–L1+PD–L2+CD14+ cells was shorter than that of patients with other types of CD14+ cells (p = 0.0023). PD–L1+PD–L2+CD14+ cells produced IL-10 and CCL1, and showed little tumoricidal activity against HepG2 cells. The tumoricidal activity of CD8+ cells from patients with PD–L1+PD–L2+CD14+ cells were suppressed by co-cultivation with CD14+ cells from the syngeneic patient. Furthermore, anti-PD-1 antibody restored their tumoricidal activity of CD8+ cells. In conclusion, some patients with HCC have PD–L1+PD–L2+CD14+ cells that suppress their antitumor response. These inhibitory functions of CD14+ cells may be associated with a poor prognosis in these patients.

Admission Low-Density Lipoprotein Cholesterol Stratified by Circulating CD14++CD16+ Monocytes and Risk for Recurrent Cardiovascular Events Following ST Elevation Myocardial Infarction: Lipid Paradox Revised.

Lower level of low-density lipoprotein cholesterol (LDL-C) is paradoxically associated with increased mortality in ST elevation myocardial infarction (STEMI) patients. The underlying mechanism remains unclear. In a cohort of 220 de novo STEMI patients receiving timely primary percutaneous coronary intervention, admission LDL-C was negatively associated with circulating CD14++CD16+ monocyte counts. Moreover, admission LDL-C < 85mg/dL was associated with increased risk for major adverse cardiovascular events (MACE) during a median follow-up of 2.7years. After categorizing the patients according to the cutoff values of 85mg/dL for LDL-C and the median for CD14++CD16+ monocytes, low LDL-C-associated MACE risk was only observed in those with high CD14++CD16+ monocyte counts (low LDL-C/high CD14++CD16+ monocytes vs. low LDL-C/low CD14++CD16+ monocytes: hazard ratio 5.38, 95% confidence interval 1.52 to 19.06, P = 0.009). This work provided the proof-of-principle evidence indicating a role of CD14++CD16+ monocytes in risk stratification of STEMI patients presenting with low LDL-C level. Graphical abstract.

PD-L1+PD-L2+ monocytes from patients with hepatocellular carcinoma may be associated with a poor prognosis

Abstract The prognosis of patients with hepatocellular carcinoma (HCC) is poor. Anti–programmed death-1 (PD-1) antibodies (Abs) has been approved to treat HCC. Some PD-1 ligands (PD-L1 and PD-L2) negative tumors respond to anti–PD-1 Abs. This response may be caused by the expression of PD-1 ligands on non-tumor cells. PD-1 ligands were recently found to be expressed on monocytes (CD14+ cells) from diverse cancer patients. In this study, we investigate the expression of PD-1 ligands on CD14+ cells from HCC patients and the role of CD14+ cells in an antitumor response. From October 2017 to June 2019, 67 patients with HCC were enrolled. The expression of PD-L1 and PD-L2 on CD14+ cells was analyzed by flow cytometry. Their prognosis was evaluated by overall survival (OS). Tumoricidal activities of both CD14+ and CD8+ cells were calculated by LDH release assay. In the results, CD14+ cells from the patients expressed PD-L1 (4.5–95.5%) and PD-L2 (1.6–90.2%). We set cut-off values as the mean values of PD-L1 (50.2%) and PD-L2 (50.5%) expression. In addition, according to the cut-off value, we classified patients as those either with PD-L1+PD-L2+CD14+ cells or other types of CD14+ cells. The OS of patients with PD-L1+PD-L2+CD14+ cells was significantly shorter than that of patients with other types of CD14+ cells (p = 0.0145). The tumoricidal activity of CD8+ cells from patients with PD-L1+PD-L2+CD14+ cells was suppressed by co-cultivation with syngeneic CD14+ cells. Furthermore, anti–PD-1 Ab restored the tumoricidal activity of CD8+ cells. In conclusions, some patients with HCC have PD-L1+PD-L2+CD14+ cells that suppress their antitumor response of CD8+ cells. These inhibitory functions of CD14+ cells may be associated with a poor prognosis in such patients.

Abstract P164: Sexual Dimorphic Role of CD14 in Dahl SS Hypertension

Previous work has implicated the immune system in potentiating salt-sensitive (SS) hypertension and kidney damage in the Dahl SS rat model. The innate immunity protein Cluster of Differentiation 14 (CD14), normally involved in bacterial responses of macrophages, has been associated with hypertension in humans. The present study tests the hypothesis that CD14 influences the extent of high-salt diet induced renal damage and hypertension in the Dahl SS rat, by modulating activation of the innate immune system. CD14 was mutated in the Dahl SS background using CRISPR-Cas9 technology, leading to the loss of CD14 protein in peritoneal macrophages (pMacs) as evidenced by mass spectrometry-based parallel reaction monitoring. pMac stimulation in vitro demonstrated altered IL-1β production in CD14-/- animals. To monitor SS phenotypes in vivo , male and female CD14+/+ and CD14-/- animals maintained on a 0.4% NaCl diet underwent carotid catheter telemetry implantation at 7 weeks of age (n=12/14). After recovery and baseline recordings, animals were switched to a 4.0% NaCl diet for 21 days. There was no significant difference in the SS increase in blood pressure or albuminuria between genotypes of males. However, female CD14-/- animals demonstrated exacerbated salt-sensitivity of blood pressure (+45mmHg) compared to wild types (+31mmHg). To determine what may mediate this difference, immune cells were isolated from the kidneys of these animals. Accordingly, males showed no difference in immune cell infiltration; whereas, female CD14-/- animals showed an elevation in the infiltration of CD11b/c+ macrophages. To determine whether knockout of CD14 in immune cells specifically was responsible for this phenotypic difference, a lethal dose of total body irradiation (11Gy) of CD14+/+ recipient animals followed by either CD14-/- or CD14+/+ bone marrow transfer experiment was done in female animals (n=6/7). Remarkably, even though all host tissue cells were wildtype, transfer of CD14-/- bone marrow recapitulated the exacerbated SS phenotypes, including increased renal infiltration of macrophages. Together, these data demonstrate that CD14 signaling in hematopoietic cells of females modulates the full extent of the immune response and blunts SS hypertension.

Abstract 21282: CD14 is a Key Mediator of Foam Cell Formation Induced by Lysophosphatidic Acid and Lipopolysaccharide

Lysophosphatidic acid (LPA), a simple lysophospholipid, has potent effects on a variety of cell types. We report here that LPA enhances lipopolysaccharide (LPS)-induced oxidized low density lipoprotein (oxLDL) uptake in mouse primary bone marrow-derived macrophages (BMMs). Our data revealed that both LPA and LPS highly induce the CD14 expression at both messenger RNA and protein levels in BMMs. The role of CD14, one component of the LPS receptor cluster, in LPA-induced biological functions has been unknown. We took several steps to examine the role of CD14 in LPA signaling pathways. Knockdown of CD14 expression nearly completely blocked LPA-, LPS- or LPA plus LPS-induced oxLDL uptake in BMMs, demonstrating for the first time that CD14 is a key mediator responsible for both LPA- and LPS-induced oxLDL uptake/foam cell formation. To determine the molecular mechanism mediating CD14's novel function, we demonstrated that both LPA and LPS significantly induce the scavenger receptor A-1 (SR-AI) expression, and depletion of CD14 levels blocked LPA/LPS-induced SR-AI expression. We further showed that the SR-AI specific antibody, which quenches SR-AI function, blocked LPA and LPS-induced foam cell formation. Thus, SR-AI is the downstream mediator of CD14 in regulating LPA-, LPS-, and LPA/LPS-induced foam cell formation. Taken together, our results provide the first experimental evidence that CD14 is a novel junctional molecule connecting both LPA and LPS pathways and is a key mediator responsible for both LPA- and LPS-induced foam cell formation. The LPA/LPS-CD14-SR-AI nexus might be the new convergent pathway, contributing to the worsening of atherosclerosis.

CD14 Plays a Protective Role in Experimental Inflammatory Bowel Disease by Enhancing Intestinal Barrier Function

Intestinal homeostasis disturbance through intestinal barrier disruption presumably plays a key role in inflammatory bowel disease (IBD) development. Genetic and candidate gene analyses in an Il10-deficient IBD mouse model system identified Cd14 as a potentially protective candidate gene. The role of Cd14 in colitis development was determined using dextran sulfate sodium (DSS)-induced acute and an Il10-deficiency-induced chronic model of intestinal inflammation. Intestinal permeability was investigated by fluorescein isothiocyanate-dextran uptake assay, quantitative RT-PCR analysis of tight junction proteins, myosin light chain kinase, and proinflammatory cytokine expression. Immunohistological staining of occludin, Ki-67, NF-κB-p65, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was performed, and intestinal inflammation severity was evaluated histologically. Untreated B6-Cd14-/- mice and wild-type controls did not differ in intestinal barrier function. However, DSS-treated Cd14-deficient and B6-Il10-/-Cd14-/- mice exhibited more severe intestinal barrier disruption, with increased histological scores and proinflammatory cytokine expression, compared to controls. Therefore, Cd14 deficiency did not influence epithelial integrity under steady-state conditions but caused intestinal barrier dysfunction under inflammation. As expected, CD14 overexpression increased barrier integrity. No difference in intestinal epithelial NF-κB translocation was observed between the investigated groups. Intestinal myosin light chain kinase expression decreased in Cd14-deficient mice under steady-state conditions and in the chronic model, whereas no difference was detected in the DSS models. Thus, CD14 plays a protective role in IBD development by enhancing intestinal barrier function.

New roles for CD14 and IL-β linking inflammatory dendritic cells to IL-17 production in memory CD4+ T cells.

Interleukin (IL)-1β has proven to be crucial in the differentiation of human and mouse Th17 cells. Although it has become evident that IL-1β has potent IL-17-inducing effects on CD4+ T cells directly, it has not yet been explored whether IL-1β can also prime dendritic cells (DCs) for a Th17 instruction program. Here, we show that human immature DCs exposed to IL-1β promote IL-17 production in human memory CD4+ T cells. IL-1β-primed DCs express high levels of CD14 that mediate IL-17 production through direct interaction with T cells. Moreover, culturing human CD4+CD45RO+ memory T cells with soluble CD14 is sufficient for the upregulation of retinoic acid-related orphan receptor-γ thymus and IL-17 production. In addition, in a human in situ model using tissue-resident skin DCs, upregulation of CD14 expression induced by IL-1β on skin residents DCs promotes IL-17 production in memory T cells; strongly suggesting the in vivo relevance of this mechanism. Our findings uncover new roles for IL-1β and CD14, and may therefore have important consequences for the development of new therapies for Th17-mediated autoimmune diseases and bacterial and fungal pathogenic infections.

Inhibition of transglutaminase 2 reduces efferocytosis in human macrophages: Role of CD14 and SR-AI receptors

Background and aimsTransglutaminase 2 (TGM2), a member of the transglutaminase family of enzymes, is a multifunctional protein involved in numerous events spanning from cell differentiation, to signal transduction, apoptosis, and wound healing. It is expressed in a variety of cells, macrophages included. Macrophage TGM2 promotes the clearance of apoptotic cells (efferocytosis) and emerging evidence suggests that defective efferocytosis contributes to the consequences of inflammation-associated diseases, including atherosclerotic lesion progression and its sequelae. Of interest, active TGM2 identified in human atherosclerotic lesions plays critical roles in plaque stability through effects on matrix cross-linking and TGFβ activity. This study explores the mechanisms by which TGM2 controls efferocytosis in human macrophages. Methods and resultsHerein we show that TGM2 increases progressively during monocyte differentiation towards macrophages and controls their efferocytic potential as well as morphology and viability. Two experimental approaches that took advantage of the inhibition of TGM2 activity and protein silencing give proof that TGM2 reduction significantly impairs macrophage efferocytosis. Among the mechanisms involved we highlighted a role of the receptors CD14 and SR-AI whose levels were markedly reduced by TGM2 inhibition. Conversely, CD36 receptor and αvβ3 integrin levels were not influenced. Of note, lipid accumulation and IL-10 secretion were reduced in macrophages displaying defective efferocytosis. ConclusionOverall, our data define a crucial role of TGM2 activity during macrophage differentiation via mechanisms involving CD14 and SR-AI receptors and show that TGM2 inhibition triggers a pro-inflammatory phenotype.

Abstract 1077: Loss of HER2 via trogocytosis by CD14+ cells in HER2-overexpressing breast cancer cells is associated with diminishing of trastuzumab-mediated antibody-dependent cellular cytotoxicity

Abstract The transfer of cell-surface membrane proteins and membrane patches from one cell to another at the time of contact, known as trogocytosis, was reported in chronic lymphocytic leukemia and multiple myeloma patients and was associated with clinical outcome. However, in solid malignant tumors, such as breast cancer, there is no evidence that trogocytosis occurs clinically thus its clinical importance has not been evaluated yet. In the current study, we found significantly high HER2 expression on tumor-infiltrated CD14+ cells as compared to control CD14+ cells of PBMCs in HER2 overexpressing breast cancer patient who had been treated with trastuzmab. Digested tumor cell suspension and its autologous PBMCs were co-cultured at 1:10 ratio with 0 and 1 μg/ml of trastuzumab as trogocytosis assay. Percentage of HER2 positive CD14+ cells was higher in the treatment of 1 μg/ml of trastuzumab as compared to that of 0 μg/ml of trastuzumab (17% and 12%, respectively) while HER2 expression of digested tumor cells was lower in 1 μg/ml of trastuzumab treatment as compared to that of 0 μg/ml of trastuzumab (18% and 25%, respectively). These findings suggested that HER2 might be transferred from HER2 overexpressing breast tumor cells to CD14+ cells, which was possibility of evidence of trogocytosis in the HER2+ breast cancer patient, and suggested that CD14+ cell might have an important role in the trogocytosis. We next define the role of CD14+ cells and CD56+ cells in the process of both trogocytosis and antibody dependent cellular cytotoxicity (ADCC) in experimental setting using SK-BR-3 and BT-474, both HER2 overexpressing human breast cancer cell lines, and MCF-7 and MDA-MB-231, both HER2 negative human breast cancer cell lines. We found that trogocytosis was observed specifically on HER2 overexpressing breast cancer cell lines in in vitro torogocytosis assay and CD14+ cells have a role for trogocytosis dominantly as compared to CD56+ cells. HER2 loss was increased as Effector / Target ratio or concentration of trastuzumab was increased. HER2 loss on target cancer cells caused by trogocytosis of CD14+ cells inhibits CD56+ cell-mediated ADCC, however when CD14+ cells are depleted, such inhibitory effects are recovered and CD56+ cells show better cytotoxicity. Currently analyzed preliminary clinical sample data and experimental data of HER2 loss via trogocytosis might explain different level of treatment response of trastuzumab in individual patients. Citation Format: Eiji Suzuki, Mariko Nishie, Kosuke Kawaguchi, Sunao Tanaka, Masakazu Toi. Loss of HER2 via trogocytosis by CD14+ cells in HER2-overexpressing breast cancer cells is associated with diminishing of trastuzumab-mediated antibody-dependent cellular cytotoxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2014-1077

Sa1782 Opposing Roles of CD14 and TLR4 in Bacterial LPS-Induced Colonocytic Apoptosis

Sa1782 Opposing Roles of CD14 and TLR4 in Bacterial LPS-Induced Colonocytic Apoptosis

LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

Treatment of cultures with toll-like receptor (TLR) ligands or cytokines has become a popular approach to investigate astrocyte neuroinflammatory responses and to simulate the neural environment in various CNS disorders. However, despite much effort, the mechanism of astrocyte activation such as their responses to the TLR ligands and IL-1 remain highly debated. We compared highly pure primary mouse and human astrocyte cultures in their ability to produce proinflammatory mediators (termed "A1") and immunoregulatory mediators (termed "A2") in response to LPS, poly IC, and IL-1 stimulation. In human astrocytes, IL-1 induced both A1 and A2 responses, poly IC induced mostly A2, and LPS induced neither. In mouse astrocytes, LPS induced mostly an A1-predominant response, poly IC induced both A1 and A2, and IL-1 neither. In addition, mouse astrocytes produce abundant IL-1 protein, whereas human astrocytes did not, despite robust IL-1 mRNA expression. Of the TLR4 receptor complex proteins, human astrocytes expressed TLR4 and MD2 but not CD14, whereas mouse astrocytes expressed all three. Mouse astrocyte CD14 (cell-associated and soluble) was potently upregulated by LPS. Silencing TLR4 or CD14 by siRNA suppressed LPS responses in mouse astrocytes. In vivo, astrocytes in LPS-injected mouse brains also expressed CD14. Our results show striking differences between human and mouse astrocytes in the use of TLR/IL-1R and subsequent downstream signaling and immune activation. IL-1 translational block in human astrocytes may be a built-in mechanism to prevent autocrine and paracrine cell activation and neuroinflammation. These results have important implications for translational research of human CNS diseases.

CD14 overexpression upregulates TNF-α-mediated inflammatory responses and suppresses the malignancy of gastric carcinoma cells

CD14 mediates the inflammatory response via recognition of lipopolysaccharide, which has been implicated in Helicobacter pylori (H. pylori) infections. Increasing evidence has suggested that CD14 status significantly influences the clinical outcome of H. pylori infection, which can result in gastric carcinoma. However, there is little evidence regarding the cellular impact and associated molecular basis of CD14 on gastric carcinoma cells. To address this question, we generated a CD14-overexpressing SGC-7901 gastric carcinoma cell line and analyzed the impact of CD14 expression. Our results revealed that cells overexpressing CD14 exhibited antitumor potential, including significantly decreased clonogenic ability, proliferation, metastatic invasion, as well as enhanced apoptosis, suggesting a tumor-suppressive role of CD14 in the cells. Intriguingly, we further discovered that CD14 overexpression activated NF-κB via upregulating its expression and simultaneously stimulating DNA binding activity. Upregulated NF-κB transcriptionally elevated a series of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12. Together, the current study utilized a CD14-overexpressing gastric cell model to determine the impacts of CD14 upregulation on cell viability, apoptosis, and migration and NF-κB-mediated inflammation.

Role of CD14 in host protection against infections and in metabolism regulation

CD14 is a glycosylphosphatidylinositol (GPI)-anchored receptor known to serve as a co-receptor for several Toll-like Receptors (TLRs) both at the cell surface and in the endosomal compartment. CD14 can be expressed by cells of both hematopoietic and non-hematopoietic origin as a cell membrane or secreted protein. Although CD14 was discovered more than 20 years ago, its activities remain largely to be defined. Most of the information available concerns CD14's role as a co-receptor working with TLR4 and facilitating cellular responses to low doses of lipopolysaccharide (LPS). Recent studies have highlighted and molecularly defined many other functions of this pattern recognition receptor (PRR). These functions include the mechanisms through which CD14 allows the activation of the TLR4-TRAM-TRIF pathway upon LPS stimulation; the capacity of CD14 to transduce a TLR4-independent signaling pathway leading to the activation of NFAT transcription factor family members with important consequences in myeloid cells; the CD14 influence on cell metabolism in conditions predisposing to obesity. In this review, we summarize recent progresses toward the molecular definition of the multiple roles exerted by CD14 in innate immune cells in response to LPS and the consequences of CD14 activation in physiologic and pathologic conditions.

Polymorphisms in the promoter of the CD14 gene and their associations with susceptibility to pulmonary tuberculosis

Although the role of CD14 in recognizing Mycobacterium tuberculosis is well-understood, the possible role of polymorphisms in susceptibility to develop tuberculosis remains unclear. This study evaluates whether there is an association of polymorphisms within the promoter of the CD14 gene with susceptibility to pulmonary tuberculosis. In a case-control study, we genotyped the eight known single nucleotide polymorphisms SNPs within the promoter of the CD14 gene of 698 Han Chinese subjects. Statistically significant differences between tuberculosis patients and healthy controls were found for G-1619A, T-1359G, A-1145G, and C-159T. The haplotype-GGGT, composed of these four SNPs, exhibited a significant association with the disease. Furthermore, expression levels of soluble CD14 were significantly higher in tuberculosis patients with the GGGT haplotype than with other haplotypes, while IgE expression levels were significantly reduced. Our results suggest that these four SNPs within the promoter of the CD14 gene are associated with susceptibility to pulmonary tuberculosis.

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

The Toll-like receptors (TLRs) 3, 7, 8 and 9 stimulate innate immune responses upon recognizing pathogen-derived nucleic acids. TLR3 is located on the cell surface and in cellular endosomes and recognizes double-stranded viral RNA or the synthetic mimic poly rI:rC. Recently, unformulated small interfering RNA (siRNA) has been reported as ligand for surface-expressed murine TLR3. Blockage of TLR3 is achieved by single-stranded DNA. We confirm and expand the observation that poly rI:rC-mediated TLR3 immune activation is blocked in a sequence-, length-, backbone- and CpG-dependent manner. However, human TLR3 is not activated by siRNA, which may be the result of differences in the amino acid composition of the TLR3 loop 1 of mice and humans. Although CD14 was previously described as a co-receptor for murine TLR3 and other nucleic acid-recognizing TLRs, human CD14 acts only as co-receptor to human TLR9, but not TLR3, TLR7 or TLR8. We show that CD14 up-regulates the TLR9 immune response of A, B and C-class oligodeoxynucleotides but down-regulates the phosphoro-diester version of B-class oligodeoxynucleotides.