The innate immune system provides a first line of defense against invading pathogens, in which the pattern recognition receptors (PRR) recognize pathogen-associated molecular patterns (PAMP) and initiate the downstream signaling pathways to eliminate the encountered pathogens. There are two main classes of such signaling pathways: NOD-like receptor (NLR) signaling pathway and Toll-like receptor (TLR) signaling pathway. The microbial pathogens under selective pressure have evolved numerous mechanisms to avoid and/or manipulate the NLR and TLR signal transduction for survival and replication. To evade the NLR signaling pathway, pathogens interfere and/or inhibit inflammasome activation in innate immune cells by producing virulence factors or reducing PAMPs expression. The mechanisms for pathogens to evade TLR signaling pathway include: inhibition of mitogen activated protein kinases (MAPKs) cascade reaction, inhibition of NF-КB activation, and interference of down-stream signal transduction by producing Toll/interleukin-1 receptor (TIR)-containing proteins which bind directly with TLRs or adaptor proteins in the signaling pathway.
Immunity, Innate ; NLR Proteins ; immunology ; Receptors, Interleukin-1 ; metabolism ; Signal Transduction ; Toll-Like Receptors ; immunology

Toll-like receptors (TLRs) are the archetypal pattern recognition receptors in sensing exogenous pathogens. Activation of TLRs is a first line of defense of the immune system, leading to the activation and recruitment of neutrophils and macrophages to sites of infection and enhances antimicrobial activity. The TLR signaling through different intracellular molecules, such as MAP kinases and IkappaB kinases which are conserved signaling elements for many receptors, leads to a distinct set of proinflammatory gene expressions. However, how these pathways differentially and precisely control the transcription of identical genes remains largely unknown. Our review focuses on the details of up-to- date signaling molecules including negative regulators and their role in controlling innate immune response. We also stress the importance of developing systemic approaches for the global understanding of TLR signaling so that appropriate drug therapeutic targets can be identified for regulating inflammatory diseases.
Adaptor Proteins, Signal Transducing/*immunology ; Animals ; Humans ; MAP Kinase Signaling System/*immunology ; Receptor Cross-Talk ; Receptors, Interleukin-1/immunology ; *Signal Transduction ; Toll-Like Receptors/*immunology

OBJECTIVETo investigate the expressions of chemokine receptors and interleukin (IL) receptors on the peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients and their correlations with clinical features as well as SLE disease activity index (SLEDAI).

METHODSThe mRNA expressions of chemokine receptors and IL receptors on PBMCs of 93 SLE patients and 30 healthy controls were detected by reverse transcription-polymerase chain reaction, including CCR2, CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCRS, CX3CR1, XCR1, IL-4R, and IL-10R. The clinical features of SLE patients were recorded. The correlations of chemokine receptors and IL receptors mRNA expressions with clinical features as well as SLEDAI were assayed using linear regression analysis.

RESULTSThe level of CCR5 mRNA in SLE patients (including active and inactive SLE) was significantly higher than that in healthy controls (P < 0.05), and there was no significant difference between active and inactive patients in this respect (P > 0.05). CX3CR1 mRNA expression significantly increased from healthy control to inactive SLE to active SLE in sequence. The others (except for CCR8, CXCR3, and IL-10R) in active SLE patients were significantly higher than those in both inactive SLE patients and healthy controls (all P < 0.05). There were positive correlations between SLEDAI and CCR2 (r = 0.424, t = 4.313, P < 0.001), CCR3 (r = 0.518, t = 5.410, P < 0.001), CCR4 (r = 0.376, t = 3.851, P < 0.001), CCR6 (r = 0.457, t = 4.513, P < 0.001), CXCR5 (r = 0.455, t = 4.629, P < 0.001), CX3CR1 (r = 0.445, t = 4.523, P < 0.001), as well as XCR1 (r = 0.540, t = 5.445, P < 0.001). And CCR5 mRNA expression level was positively correlated with IL-4R mRNA (r = 0.313, t = 2.353, P < 0.05). The patients with myositis and cutaneous vasculitis simultaneously showed lower levels of CCR5 and CX3CR1, and CCR5 expression was negatively correlated with the scores of SLEDAI in SLE cases accompanied by photosensitivity (r = 0.426, t = -2.155, P < 0.05).

CONCLUSIONIncreased expressions of CCR5 and CX3CR1 on PBMCs may be indicators in clinical survey for SLE.

Adolescent ; Adult ; CX3C Chemokine Receptor 1 ; Child ; Female ; Humans ; Leukocytes, Mononuclear ; immunology ; Lupus Erythematosus, Systemic ; etiology ; immunology ; Male ; Middle Aged ; RNA, Messenger ; blood ; Receptors, CCR5 ; genetics ; Receptors, Chemokine ; genetics ; Receptors, Interleukin-10 ; genetics ; Receptors, Interleukin-4 ; genetics

OBJECTIVE: To investigate the expression and role of Interleukin-33 (IL-33) and ST2 in the nasal polyps of human Eosinophilic and non-Eosinophilic chronic rhinosinusitis with nasal polyps (ECRS and non-ECRS). METHOD: IL-33 and ST2 protein expression in nasal polyps of ECRS and non-ECRS as well as in seemingly normal mucosa of the inferior turbinate tissue was investigated by immunohistochemical staining and messenger RNA (mRNA) expression of IL-33 and ST2 was assessed by realtime polymerase chain reaction (PCR) in 27 subjects with ECRS, 33 subjects with non-ECRS, and 11 control subjects. RESULT: (1) The ST2 was found both in nasal polyps of ECRS and non-ECRS,especially in ECRS, yet hardly found in the normal mucosa of the inferior turbinate tissue; (2) The expression of ST2 mRNA in nasal polyps of ECRS was higher than that in non-ECRS and normal inferior turbinate tissue, and the difference was both prominent in statistics (P<0.01); (3) The expression patterns of IL-33 at both mRNA and protein levels were not significantly different among the three groups (P>0.05). CONCLUSION The IL-33 and its receptor ST2 were both expressed in human nasal polyps including ECRS and non-ECRS, meanwhile the expression patterns of ST2 at both mRNA and protein levels were significantly higher in nasal polyps of ECRS. The current study suggests that IL-33 and its receptor ST2 may play important roles in the pathogenesis of chronic rhinosinusitis with nasal polyps, especially in ECRS through the increased expression of ST2 in Eosinophils as a hypothesis.
Chronic Disease ; Eosinophils ; immunology ; Humans ; Interleukin-1 Receptor-Like 1 Protein ; Interleukin-33 ; metabolism ; Nasal Mucosa ; metabolism ; Nasal Polyps ; immunology ; RNA, Messenger ; Real-Time Polymerase Chain Reaction ; Receptors, Cell Surface ; metabolism ; Rhinitis ; immunology ; Sinusitis ; immunology ; Turbinates ; metabolism

OBJECTIVETo study whether infantile wheezing pneumonia has similar immune mechanisms to asthma by determining the levels of serum inflammatory factors in wheezing infants with community-acquired pneumonia (CAP).

METHODSForty-two infants with CAP but without wheezing, 47 infants with CAP and wheezing, and 30 healthy infants as a control were recruited in the study. The peripheral blood levels of C-reactive protein, procalcitonin, soluble triggering receptor expressed on myeloid cell-l, interferon-γ, interleukin-4, interleukin-10, and periostin were compared in the three groups.

RESULTSThe serum levels of procalcitonin, soluble triggering receptor expressed on myeloid cell-l, interleukin-4 and interleukin-10 in the two CAP groups were higher than in the control group (P<0.05). The ratio of interferon-γ/interleukin-4 in the wheezing pneumonia group was lower than in the non-wheezing pneumonia and control groups (P<0.05). The serum level of periostin in the wheezing pneumonia group was higher than in the non-wheezing pneumonia and control groups (P<0.05).

CONCLUSIONSThe unbalanced ratio of interferon-γ/interleukin-4 and airway eosinophilic inflammation in wheezing infants with pneumonia suggest infantile pneumonia with wheezing may has similar immune mechanisms to asthma.

Child, Preschool ; Community-Acquired Infections ; immunology ; Female ; Humans ; Infant ; Interferon-gamma ; blood ; Interleukin-10 ; blood ; Interleukin-4 ; blood ; Male ; Membrane Glycoproteins ; blood ; Pneumonia ; immunology ; Receptors, Immunologic ; blood ; Respiratory Sounds ; immunology ; Triggering Receptor Expressed on Myeloid Cells-1

We studied the immunogenicity of pseudorabies virus gC DNA vaccination by fusing the murine complement C3d receptor binding domain. First, pseudorabies virus gC gene was linked to four copies of C3d receptor binding domain (M284), and then cloned into the vector pcDNA3.1 to construct the recombinant plasmid sgC-M284. Through the experiment of immunized BALB/c mice, we found that the enzyme linked immunosorbent assay (ELISA) antibody titer for sgC-M284 was 17-fold higher than that for sgC alone, and protective rate of mice was augmented from 25% to 88% after lethal dose PrV (316 LD50) challenge. In addition, the IL-4 levels for sgC-M284 immunization approached that for the pseudorabies virus inactivated vaccine. In conclusion, we demonstrated murine C3d receptor binding domain fusion significantly increased Th2-biased immune response by inducing IL-4 production.
Adjuvants, Immunologic ; physiology ; Animals ; Antibody Formation ; immunology ; Binding Sites ; Cloning, Molecular ; Complement C3d ; genetics ; immunology ; Herpesvirus 1, Suid ; genetics ; immunology ; Interleukin-4 ; immunology ; Mice ; Mice, Inbred BALB C ; Pseudorabies Vaccines ; immunology ; Receptors, Complement 3d ; genetics ; Recombinant Proteins ; biosynthesis ; genetics ; immunology ; Swine ; Vaccines, DNA ; immunology ; Viral Envelope Proteins ; pharmacology ; Viral Fusion Proteins ; immunology

The aims of this study were to investigate the relationships between the production of interleukin-1 (IL-1), and IL-6 system by whole blood cells, and bone mineral density (BMD), and polymorphisms in IL-1 system and IL-6 gene in postmenopausal Korean women. The production of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r) by lipopolysaccharide-stimulated whole blood cells was measured by ELISA in 110 subjects. Serum osteocalcin, C-telopeptide of type I collagen, and BMD at lumbar spine and proximal femur were measured. IL-1alphaC(-889)T polymorphism, IL-1beta C(-511)T polymorphism, 86-base pair variable number tandem repeat polymorphism in the IL-1ra gene, and IL-6 C(-634)G polymorphism were analyzed. The production of IL-1beta correlated positively with BMD at femoral neck, whereas the production of other ILs did not correlate with BMD at the skeletal sites examined. No significant differences in the production of ILs were observed among normal, osteopenic and osteoporotic postmenopausal women, and among the different IL system polymorphisms groups studied. No correlation between bone turnover markers and the production of ILs was noted. In conclusion IL-1beta may regulate bone metabolism at femoral neck, and the IL system polymorphism do not affect the production of ILs by whole blood cells.
Aged ; Blood Cells/drug effects/immunology ; Bone Density/*genetics/*immunology ; Bone Diseases, Metabolic/blood/genetics/immunology ; Cytokines/*biosynthesis/blood ; Female ; Humans ; In Vitro ; Interleukin-1/biosynthesis/blood/genetics ; Interleukin-6/biosynthesis/blood/genetics ; Interleukins/*genetics ; Lipopolysaccharides/pharmacology ; Middle Aged ; Osteoporosis, Postmenopausal/blood/genetics/immunology ; *Polymorphism, Genetic ; Receptors, Interleukin-6/biosynthesis/blood/genetics ; Research Support, Non-U.S. Gov't ; Sialoglycoproteins/biosynthesis/blood/genetics

OBJECTIVETo investigate the role of triggering receptors expressed on myeloid-1(TREM-1) in innate response to Porphyromonas gingivalis(Pg) in mice macrophages and its potential role in periodontitis development.

METHODSPeritoneal macrophages from mice were harvested, separated and cultured, then challenged with viable Pg. Transcription and protein expression in macrophages were assessed with real time PCR and flow cytometry respectively.LP-17 peptide (10, 100 and 1000 µg/L) was utilized to block TREM-1, and tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected by enzyme linked absorbent analysis.

RESULTSAt 2 h after Pg challenge, transcription of TREM-1 was significantly up-regulated after Pg challenge[(7.99 ± 1.11) fold vs blank]. At 24 h after bacteria infection, increased TREM-1 expression was demonstrated by flow cytometry, with mean fluorescent intensity increasing from (7.05 ± 1.85) in blank group to (13.17 ± 2.33) in experimental group. Proinflammatory cytokine (TNF-α and IL-6) production was significantly decreased after blocking TREM-1 by LP-17 peptide(100 and 1000 µg/L).

CONCLUSIONSTREM-1 enhanced innate immune response to Pg in macrophages, which may facilitate periodontitis development.

Animals ; Cells, Cultured ; Interleukin-6 ; metabolism ; Macrophages, Peritoneal ; cytology ; immunology ; metabolism ; Membrane Glycoproteins ; metabolism ; Mice ; Mice, Inbred C57BL ; Peptides ; pharmacology ; Porphyromonas gingivalis ; immunology ; Receptors, Immunologic ; metabolism ; Triggering Receptor Expressed on Myeloid Cells-1 ; Tumor Necrosis Factor-alpha ; metabolism ; Up-Regulation

Interleukin (IL) 33, a member of the IL-1 superfamily, is an "alarmin" protein and is secreted in its active form from damaged cells undergoing necrotic cell death. Mast cells are one of the main effector cell types in allergic disorders. They secrete a variety of mediators, including T helper 2 cytokines. As mast cells have high-affinity IgE receptors (FcepsilonRI) on their surface, they can capture circulating IgE. IgE-bound mast cells degranulate large amounts of histamine, heparin, and proteases when they encounter antigens. As IL-33 is an important mediator of innate immunity and mast cells play an important role in adaptive immune responses, interactions between the two could link innate and adaptive immunity. IL-33 promotes the adhesion of mast cells to laminin, fibronectin, and vitronectin. IL-33 increases the expression of adhesion molecules, such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, in endothelial cells, thus enhancing mast cell adhesion to blood vessel walls. IL-33 stimulates mast cell proliferation by activating the ST2/Myd88 pathway; increases mast cell survival by the activation of survival proteins such as Bcl-XL; and promotes the growth, development, and maturation of mast cell progenitors. IL-33 is also involved in the activation of mature mast cells and production of different proinflammatory cytokines. The interaction of IL-33 and mast cells could have important clinical implications in the field of clinical urology. Epithelial dysfunction and mast cells could play an important role in the pathogenesis of interstitial cystitis. Urinary levels of IL-33 significantly increase in patients with interstitial cystitis. In addition, the number of mast cells significantly increase in the urinary bladders of patients with interstitial cystitis. Therefore, inhibition of mast cell activation and degranulation in response to increase in IL-33 is a potential therapeutic target in the treatment of interstitial cystitis.
Adaptive Immunity* ; Allergy and Immunology ; Blood Vessels ; Cell Death ; Cystitis, Interstitial ; Cytokines ; Endothelial Cells ; Fibronectins ; Heparin ; Histamine ; Humans ; Immunity, Innate ; Immunoglobulin E ; Interleukin-1 ; Interleukins ; Laminin ; Mast Cells* ; Peptide Hydrolases ; Receptors, IgE ; Urinary Bladder ; Urology ; Vascular Cell Adhesion Molecule-1 ; Vitronectin

GITR (glucocorticoid-induced TNF receptor) is a recently identified member of the TNF receptor superfamily. The receptor is preferentially expressed on CD4+CD25+ regulatory T cells and GITR signals break the suppressive activity of the subset. In this study, we wanted to reveal the in vivo function of GITR in herpes simplex virus type 1 (HSV-1) infection. A single injection of anti-GITR mAb (DTA-1) immediately after viral infection significantly increased the number of CD4+ and CD8+ T cells expressing CD25, an activation surface marker, and secreting IFN-gamma. We confirmed these in vivo observations by showing ex vivo that re-stimulation of CD4+ or CD8+ T cells with a CD4+ or CD8+ T-cell-specific HSV-1 peptide, respectively, induced a significant elevation in cell proliferation and in IFN-gamma secretion. Our results indicate that GITR signals play a critical role in the T-cell immunity to HSV-1.
Animals ; Antibodies, Monoclonal/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Female ; Glucocorticoids/*pharmacology ; Herpes Simplex/*immunology ; Herpesvirus 1, Human/pathogenicity ; *Immunity, Cellular ; Interferon Type II/secretion ; *Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Peptide Fragments/metabolism ; Receptors, Interleukin-2/metabolism ; Receptors, Nerve Growth Factor/genetics/immunology/*metabolism ; Receptors, Tumor Necrosis Factor/genetics/immunology/*metabolism ; Research Support, Non-U.S. Gov't ; T-Lymphocytes/*immunology/metabolism/virology