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Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory

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Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory 0031-3998/09/6602-0179 Vol. 66, No. 2, 2009 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2009 International Pediatric Research Foundation, Inc. Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates EVA LEVY, GEORGINA XANTHOU, EFTICHIA PETRAKOU, VASSILIKI ZACHARIOUDAKI, CHRISTOS TSATSANIS, SPYROS FOTOPOULOS, AND MARIETTA XANTHOU Neonatal Immunology Laboratory [E.L., E.P., S.F., M.X.], B’Neonatal Intensive Care Unit (NICU), “Aghia Sophia” Children’s Hospital, Athens 115 27, Greece; Cellular Immunology Laboratory [G.X.], Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece; Department of Clinical Chemistry [V.Z., C.T.], University of Crete, Crete 71003, Greece ABSTRACT: During infections, pathogens bind to toll-like receptor but lacks an intracellular component and is, thus, incapable of (TLR)4 and CD14 receptors and induce cytokine release, leading to signaling. MD2 is a molecule necessary for LPS recognition inflammation. Here, we investigated TLR4 and CD14 expression on by TLR4, which also cannot mediate signaling. TLR4, upon peripheral blood leukocytes (PBLs) and their roles in lipopolysac- LPS binding, leads to intracellular activation of mitogen- charide (LPS)-induced cytokine and chemokine release. Full-term activated protein kinase and nuclear factor-␬B that mediate and preterm neonates and adults were studied. PBLs were pretreated with anti-TLR4– and anti-CD14–blocking antibodies and stimulated the transcription of proinflammatory cytokine and chemokine with LPS. Cytokine and chemokine levels were measured in super- genes (4). TLR4 signaling also activates DCs that subse- natants. TLR4, CD14 expression, and LPS-induced CXCL8 release quently present pathogenic peptides to T lymphocytes and, were higher in neonates, possibly contributing to aberrant inflamma- thus, stimulate T-cell–mediated immunity (5). tion. TLR4 blockade resulted in approximately 3-fold greater sup- The specific roles of TLR4 and CD14 in LPS-induced pression of LPS-induced CXCL8 release in preterm neonates (38%) inflammatory responses by neonatal leukocytes remain not ϳ than in adults (14%). CD14 blockade ( 80%) in neonates induced clearly defined. Studies in neonates regarding TLR4 and approximately 3-fold greater inhibition of CXCL8 release, compared CD14 expression on peripheral blood monocytes have gener- with anti-TLR4 (ϳ30%). Anti-TLR4 partly (50–60%) inhibited ated contradictory data, showing either similar (6,7) or lower IL-10 and TNF-␣, whereas anti-CD14 completely suppressed their release. Our findings reveal that neonates depend more on TLR4 for (8–10) TLR4 and CD14 baseline levels, compared with CXCL8 release. Furthermore, neonatal LPS-induced CXCL8 release, adults. Additionally, other reports have demonstrated that apart from TLR4/CD14-mediated signaling, is regulated by LPS stimulation of neonatal monocytes with LPS in vitro induces interactions with other TLRs and/or immune receptors. IL-10 and increased TLR4 and CD14 levels, which, however, remain TNF-␣ release depends on LPS binding not only to CD14/TLR4 but lower than those of adults (7,9,10). In contrast, a recent study also to CD14 associated with another TLR. Our findings reveal the by Yerkovich et al. (11) showed increased TLR4 expression contribution of TLR4 and CD14 in neonatal cytokine and chemokine upon LPS stimulation in neonates, emphasizing the contro- release and could aid in design of antagonists to prevent harmful versy in the current literature. inflammation. (Pediatr Res 66: 179–184, 2009) During neonatal infections, an exacerbated inflammatory eonates are highly susceptible to Gram-negative bacteria response often occurs inducing the enhanced release of proin- N that induce high morbidity and mortality. The principal flammatory cytokines and chemokines, which may lead to pathogenic agent involved in neonatal sepsis induced by Gram- septic shock and death (12,13). In fact, expression levels of negative bacteria is endotoxin lipopolysaccharide (LPS), an es- TLR4 control the magnitude of the response to LPS. This was sential component of their surface. Defense against pathogens is shown in transgenic animals overexpressing TLR4 that are offered by immune cells, such as granulocytes, monocytes, and more sensitive to endotoxin (14). We, thus, hypothesized that dendritic cells (DCs), which express pattern-recognition recep- the increased inflammation observed during severe neonatal tors (PRRs) that recognize specific structures present on micro- infections with Gram-negative bacteria is, at least partly, due organisms, termed pathogen-associated molecular patterns to an enhanced expression and/or function of CD14 and TLR4 (PAMPs) (1). Binding of PAMPs to PRRs triggers antimicrobial on innate immune cells. To address this, we investigated the responses to combat the infection (1,2). expression patterns of TLR4 and CD14 on peripheral blood LPS is one of the best characterized PAMPs that binds to leukocytes (PBLs) of preterm and full-term neonates. In ad- the CD14/toll-like receptor (TLR)4/MD2 complex of PRRs dition, we studied the roles of TLR4 and CD14 in cytokine and activates intracellular signaling (3). CD14 binds to LPS and chemokine release by neonatal PBLs after LPS stimula- tion, using specific blocking antibodies. Received November 4, 2008; accepted March 19, 2009. Correspondence: Marietta Xanthou, M.D., Neonatal Immunology Laboratory, B’ Abbreviations: BW, birth weight; DC, dendritic cell; GA, gestational age; NICU, “Aghia Sophia” Children’s Hospital, Goudi, Athens 115 27, Greece; e-mail: LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; [email protected] Supported by a research grant obtained from “Aghia Sophia” Children’s Hospital. PBLs, peripheral blood leukocytes; PRR, pattern-recognition receptor; TLR, Eva Levy and Georgina Xanthou contributed equally to this work. toll-like receptor 179 180 LEVY ET AL. PATIENTS AND METHODS (data not shown). TLR4 baseline (before LPS stimulation) levels were significantly greater on monocytes from preterm and full- Study population. Thirty preterm neonates [birth weight (BW) 1850 ϭ ϭ (1500–2204 g), gestational age (GA) 33 (32–34 wk)], 30 full-term neonates term neonates, compared with adults (p 0.004 and p 0.016, [BW 3210 (3210–3850 g), GA 38 (37–39 wk)], and 30 adults were included respectively), (Fig. 1A). After stimulation with LPS, TLR4 ex- in the study. All neonates and adults were healthy and exhibited no signs of pression was substantially increased in all groups (compared with hypoxia or asphyxia or infections. Peripheral blood samples were obtained from neonates between the 5th and the 15th postnatal days. We obtained nonstimulated cells), and it remained significantly greater in samples only after the 5th day because during the first postnatal days, full-term neonates compared with adults (p ϭ 0.009; Fig. 1A). adaptations of various neonatal functions to the extrauterine life are taking CD14 baseline levels were significantly greater in full-term ne- place. Moreover, we did not obtain any samples beyond the 15th postnatal day Ͻ because we aimed to confine our study to the early neonatal period. Neonates onates compared with those of adults (p 0.0001; Fig. 1B). with evidence of major congenital malformations, inborn errors of metabo- After stimulation with LPS, CD14 expression was increased in lism, and those who had received immunotherapy were excluded from all groups, and it remained significantly greater in full-term enrolment. The study was approved by the Hospital Research Ethical Com- Ͻ mittee and informed written parental consent was obtained before neonates neonates, compared with adults (p 0.001; Fig. 1B). were entered into the study. Overall, enhanced TLR4 and CD14 expression was ob- Culture and stimulation of peripheral blood samples. Peripheral blood served in neonatal peripheral blood monocytes and this may samples were collected from neonates and adults and cultured in flat- bottomed 48-well cell culture plates in 10% FBS, 1% penicillin or strepto- participate in the exacerbated inflammatory response often mycin in RPMI 1640 ϩ GlutaMAX (GIBCO BRL, Carlsbad, CA), at 37°C, occurring during neonatal infections. and 5% CO2. Samples were cultured either with medium or with 1000 ng/mL Elevated CXCL8 levels in neonatal whole blood cells upon of LPS (Sigma Chemical Co., St. Louis, MO) for the study of receptor expression and cytokine release. For the investigation of receptor expression, LPS stimulation. We next investigated the LPS-induced re- samples were stimulated for 4 h with LPS. For analysis of cytokine release, lease of CXCL8, TNF-␣, and IL-10 by PBLs from neonates samples were stimulated with LPS either for 4 h (CXCL8, TNF-␣) or for 24 h and adults. In the absence of LPS, CXCL8, TNF-␣, and IL-10 (IL-10). An ultrapure preparation of LPS was used in all experiments, because previous reports have indicated that certain LPS preparations contain con- levels were undetectable in whole blood culture supernatants taminants that can induce nonspecific signaling (15,16). For blocking studies, (Fig. 2). Stimulation of PBLs with LPS resulted in increased whole blood samples were pretreated with anti-TLR2, anti-TLR4 (1 ␮g/100 ␮L, levels of CXCL8, TNF-␣, and IL-10 in all groups studied (Fig. eBiosciences, San Diego, CA), and anti-CD14 (5 ␮L/100 ␮L, Beckman Coulter, Miami, FL) blocking antibodies, or isotype (Ig) control for 30 min and then 2). CXCL8 release by PBLs upon LPS stimulation was sig- stimulated with 10 ng/mL LPS. Dose-response studies were performed with nificantly greater in both preterm and full-term neonates, anti-TLR4– and anti-CD14–blocking antibodies to identify the optimal antibody compared with adults (p ϭ 0.005 and p ϭ 0.0001, respec- concentration. Treatment of the THP-1 human monocytic cell line. The THP-1 human tively; Fig. 2A). No significant differences were observed in monocytic cell line was grown in RPMI 1640 medium, containing 2 mM the release of TNF-␣ and IL-10 after LPS stimulation among L-glutamine, 15 mM HEPES, 100 U/mL penicillin, 0.1 mg/mL streptomycin, the groups studied (Fig. 2B and C, respectively). 10% FBS (Invitrogen, Carlsbad, CA), at 5% CO2 and 37°C, as previously described (17).
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