Chronic rhinosinusitis（CRS） is a chronic inflammation of the nasal cavity and sinus mucosa, which is mainly characterized by nasal obstruction, runny nose, headache and hyposmia. Due to complex mechanisms, CRS can be divided into different clinical phenotypes and inflammatory endotypes. Approximately 80% of chronic rhinosinusitis with nasal polyps（CRSwNP） patients present with type Ⅱ inflammation. IL-4 and IL-13 are the key factors in the process of type Ⅱ inflammation, and drugs targeting IL-4/IL-13 provide new options for the treatment of CRSwNP. Therefore, this article mainly reviews the application of anti-IL-4 /IL-13 monoclonal antibody in CRSwNP.
Humans ; Nasal Polyps/therapy* ; Sinusitis/therapy* ; Chronic Disease ; Interleukin-13/antagonists & inhibitors* ; Antibodies, Monoclonal/therapeutic use* ; Interleukin-4/antagonists & inhibitors* ; Rhinitis/drug therapy* ; Rhinosinusitis

OBJECTIVE: To investigate the role of cathepsin B in hepatic Kupffer cells (KCs) in activating Toll-like receptor 4(TLR- 4)-independent inflammatory pathways in mice with lipopolysaccharide (LPS)-induced sepsis. METHODS: Eighteen wild-type (WT) mice and 18 TLR4-knockout (TLR4) mice were both divided into 3 groups for intraperitoneal injections of a lethal dose (54 mg/kg) of LPS, LPS and CA-074(a cathepsin B inhibitor), or normal saline, and the survival of the mice were observed. Another 36 WT mice and 36 TLR4mice were also divided into 3 groups and subjected to intraperitoneal injections of normal saline, 20 mg/kg LPS, or LPS with CA-074 pretreatment.After the treatments, KCs were collected from the mice for assessing the protein level and activity of cathepsin B.The histopathological changes of the liver were observed with HE staining, and the serum levels of IL-1α, IL-1β, TNF-α and IL-18 were detected. RESULTS: Compared with the WT mice,TLR4mice receiving the lethal dose of LPS had significantly longer survival time (up to 84 h) after the injection,but were still unable to fully resist LPS challenge.CA-074 pretreatment prolonged the survival time of WT mice and TLR4mice to 60 h and 132 h,respectively.In the mouse models of sepsis,20 mg/kg LPS induced significantly enhanced activity of cathepsin B without affecting its expression level in the KCs (<0.05) and increased the serum levels of the inflammatory cytokines.CA-074 pretreatment of the mice obviously lessened the detrimental effects of LPS in TLR4mice by significantly lowering cathepsin B activity in the KCs,alleviating hepatocyte apoptosis and reducing the serum levels of inflammatory cytokines. CONCLUSIONS Cathepsin B plays an important role in activating TLR4-independent inflammatory pathways in mice with LPS-induced sepsis.
Animals ; Cathepsin B ; antagonists & inhibitors ; physiology ; Dipeptides ; pharmacology ; Gene Knockout Techniques ; Hepatocytes ; Inflammation ; metabolism ; Interleukin-18 ; blood ; Interleukin-1alpha ; blood ; Interleukin-1beta ; blood ; Kupffer Cells ; metabolism ; Lipopolysaccharides ; Liver ; pathology ; Mice ; Sepsis ; etiology ; metabolism ; Toll-Like Receptor 4 ; genetics ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVECelastrol has been established as a nuclear factor-κB (NF-κB) activation inhibitor; however, the exact mechanism behind this action is still unknown. Using text-mining technology, the authors predicted that interleukin-1 receptor-associated kinases (IRAKs) are potential celastrol targets, and hypothesized that targeting IRAKs might be one way that celastrol inhibits NF-κB. This is because IRAKs are key molecules for some crucial pathways to activate NF-κB (e.g., the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily).

METHODSThe human hepatocellular cell line (HepG2) treated with palmitic acid (PA) was used as a model for stimulating TLR4/NF-κB activation, in order to observe the potential effects of celastrol in IRAK regulation and NF-κB inhibition. The transfection of small interfering RNA was used for down-regulating TLR4, IRAK1 and IRAK4, and the Western blot method was used to detect changes in the protein expressions.

RESULTSThe results showed that celastrol could effectively inhibit PA-caused TLR4-dependent NF-κB activation in the HepG2 cells; PA also activated IRAKs, which were inhibited by celastrol. Knocking down IRAKs abolished PA-caused NF-κB activation.

CONCLUSIONThe results for the first time show that targeting IRAKs is one way in which celastrol inhibits NF-κB activation.

Hep G2 Cells ; Humans ; Interleukin-1 Receptor-Associated Kinases ; antagonists & inhibitors ; NF-kappa B ; antagonists & inhibitors ; metabolism ; Phosphorylation ; Toll-Like Receptor 4 ; antagonists & inhibitors ; physiology ; Triterpenes ; pharmacology

OBJECTIVE: To explore the expression and significance of vasoactive intestinal peptide and Pituitary adenylate cyclase activiting polypeptide (VIP/PACAP) of nasal mucosa in rats with allergic rhinitis (AR), and the function of botulinum toxin-A(BTX-A) to inhibit the expression of VIP/PACAP in AR. METHOD: Thirty Sprague-Dawley rats were randomly divided into 3 groups, which were the AR group, the intervention group, and the control group. In the AR group, ovalbumin was used to sensitize healthy rats. In the intervention group, BTX-A was dripped into the nasal cavity of AR rats 7 times. In the control group, only physiological saline was used to drip into the nasal cavity of AR rats. Changes of the rats' behavior were observed. ELISA were used to detected the concentration variation of serum IFN-γ and IL-4. Histopathology and immunohistochemistry were employed to observe morphology in the rats' nasal mucosal and the expression of VIP/PACAP. Statistical analysis was also made. RESULT: (1)The typical symptoms marks of nasal scratching, sneezing, nasal blockage and rhinorrhea of AR group (7.5 ± 0.50) were higher than intervention group (1 ± 0.27) and control group (0.8 ± 0.31). (2) Comparing to intervention group and control group, the serm IFN-γ of the AR group obvious reduced (P < 0.05), the serm IL-4 of the AR group obvious rose (P < 0.01), and the serm Th1/Th2 (IFN-γ/IL-4) of the AR group obvious reduced (P < 0.01). (3) Comparing to intervention group and control group, the cilium loss, inflammatory cells infiltration, and inflammatory cells exudation of nasal mucosa in AR group were more obviously (P < 0.01), and the intervention group of the 3 indexes was obviously than control group. (4) The expression of VIP in the rats' nasal mucosa of the AR group (13.27 ± 2.74) were more intense than intervention group (5.21 ± 2.18) and control group (3.56 ± 5.30) (P < 0.01), and the expression of PACAP in the rats' nasal mucosa of the AR group (20.97 ± 2.14) were more intense than intervention group (6.33 ± 3.04) and control group (4.63 ± 1.25) (P < 0.01). (5) In all the 3 groups, there was positive correlation between expression of negative in VIP/PACAP and Thl/Th2 cell infiltration(r were respectively -0.340 and -0.223, P < 0.05). CONCLUSION The VIP/PACAP in the rats' nasal mucosa may play an important role in pathogenesis of AR, and BTX-A could improve the symptoms of AR through inhibition of the expression of VIP/ PACAP.
Animals ; Botulinum Toxins, Type A ; pharmacology ; Disease Models, Animal ; Interferon-gamma ; blood ; Interleukin-4 ; blood ; Nasal Mucosa ; drug effects ; metabolism ; Ovalbumin ; Paranasal Sinuses ; Pituitary Adenylate Cyclase-Activating Polypeptide ; antagonists & inhibitors ; metabolism ; Rats ; Rats, Sprague-Dawley ; Rhinitis, Allergic ; drug therapy ; Vasoactive Intestinal Peptide ; antagonists & inhibitors ; metabolism

OBJECTIVETo investigate the effects of antihistamine treatment on immune function in rats with experimental hepatitis.

METHODSThirty Wistar rats were randomly allocated into three groups:experimental hepatitis group (EH group), antihistamine treatment group (AH group) and normal control group (NC group). Rats in the EH group received the subcutaneous injection of 40% carbon tetrachloride oil solution and were fed on diet with low-protein, low-choline, high-fat and high-alcohol,while rats in the AH group received antihistamine treatment(ketotifen + vitamin C) additionally.They were sacrificed after 4 weeks, and the levels of serum alanine aminotransferase(ALT), total bilirubin (TBil), histamine(HA), IFNgamma, IL-12, IL-4 and IL-10 were determined. The levels of IL-12 mRNA and IFN-gamma mRNA in liver tissue were determined via real-time reverse transcriptional polymerase chain reaction(RT-PCR).

RESULTS(1) Compared to the NC group, in the EH group, the levels of ALT, TBil, and circulating and intrahepatic HA were significantly increased(P less than 0.05); intrahepatic HA were significantly decreased(P less than 0.05) after antihistamine treatment. (2) Compared to the NC group, in the EH group, the levels of IL-4, IL-10 were significantly increased((0.504+/-0.202)ng/ml and (29.025+/-1.478) pg/ml vs (0.811+/-0.244)ng/ml and (33.72+/-4.293)pg/ml respectively, P less than 0.05), and the levels of IL-12 were decreased ((6.515+/-2.893)pg/ml vs (3.519+/-1.113)pg/ml, P less than 0.05); and after antihistamine treatment the levels of IL-4 and IL-10 were significantly decreased (were (0.423+/-0.168)ng/ml and (30.412+/-3.275)pg/ml, P less than 0.05), the levels of IL-12 were significantly increased (P less than 0.05), but the level of IFNgamma had no significance (P more than 0.05). The levels of intrahepatic IL-12 mRNA and IFNgamma mRNA had similar results.

CONCLUSIONAntihistamine treatment may improve liver function and correct Th1/Th2 unbalance.

Animals ; Ascorbic Acid ; pharmacology ; Disease Models, Animal ; Hepatitis ; immunology ; metabolism ; therapy ; Histamine Antagonists ; pharmacology ; Interferon-gamma ; metabolism ; Interleukin-10 ; metabolism ; Interleukin-12 ; metabolism ; Interleukin-4 ; metabolism ; Ketotifen ; pharmacology ; Liver ; drug effects ; metabolism ; Male ; Rats ; Rats, Wistar ; Th1-Th2 Balance ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVE: To observe the expression of progesterone receptor (PR), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX-2) induced by lipopolysaccharide (LPS) or Toll-like receptor 4 antagonist (TLR4 mAb) in decidual cells in vitro, and then to explore the effect of LPS and its antagonist on PR of decidual cells and the relation between PR and inflammatory cytokines. METHODS: We isolated and cultured human decidua of early abortion in the sterile state. When the cells passaged to the 4th generation, the cells were randomly divided into 6 pore plates: A control group was added the culture medium alone; experimental group I was added 100 ng/mL of LPS; experimental group II was add 1 μg/mL of TLR4 mAb; experimental group III was added 3 μg/ mL of TLR4 mAb; experimental group IV was added 1 μg/mL of TLR4 mAb pretreatment for 24 h, and then 100 ng/mL LPS; and experimental group V was added 3 μg/mL of TLR4 mAb pretreatment for 24 h, and then 100 ng/mL LPS for 24 h culture. Subsequently, HE staining and immunofluorescence were used to observe the morphology and identify the purity of decidual cells in the 6 groups. The levels of mRNA expression of PR, IL-1β, and COX-2 were detected by reverse transcription PCR (RT-PCR). RESULTS: LPS reduced the mRNA expression of PR (P<0.05), increased the mRNA expression of IL-1β and COX-2 (P<0.05). TLR4 mAb increased the mRNA expression of PR (P<0.05) and reduced the mRNA expression of IL-1β (P<0.05) after LPS-stimulated decidual cells. High concentrations of TLR4 mAb reduced the mRNA expression of COX-2 (P<0.05) after LPS stimulated decidual cells. CONCLUSION The mRNA expression of PR is reduced, and the mRNA expressions of IL-1β and COX-2 are increased after LPS-stimulated decidual cells in vitro. TLR4 mAb antagonize the role of LPS on PR, IL-1β, and COX-2.
Adult ; Cells, Cultured ; Cyclooxygenase 2 ; genetics ; metabolism ; Decidua ; cytology ; metabolism ; Female ; Humans ; Interleukin-1beta ; genetics ; metabolism ; Lipopolysaccharides ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Receptors, Progesterone ; genetics ; metabolism ; Toll-Like Receptor 4 ; antagonists & inhibitors ; Young Adult

Microglial cells are the resident innate immune cells that sense pathogens and tissue injury in the central nervous system (CNS). Microglial activation is critical for neuroinflammatory responses. The synthetic compound 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139) is a novel chalcone-derived compound. In this study, we investigated the effects of DK-139 on Toll-like receptor 4 (TLR4)-mediated inflammatory responses in BV2 microglial cells. DK-139 inhibited lipopolysaccharide (LPS)-induced TLR4 activity, as determined using a cell-based assay. DK-139 blocked LPS-induced phosphorylation of IkappaB and p65/RelA NF-kappaB, resulting in inhibition of the nuclear translocation and trans-acting activity of NF-kappaB in BV2 microglial cells. We also found that DK-139 reduced the expression of NF-kappaB target genes, such as those for COX-2, iNOS, and IL-1beta, in LPS-stimulated BV2 microglial cells. Interestingly, DK-139 blocked LPS-induced Akt phosphorylation. Inhibition of Akt abrogated LPS-induced phosphorylation of p65/RelA, while overexpression of dominant-active p110CAAX enhanced p65/RelA phosphorylation as well as iNOS and COX2 expression. These results suggest that DK-139 exerts an anti-inflammatory effect on microglial cells by inhibiting the Akt/IkappaB kinase (IKK)/NF-kappaB signaling pathway.
Animals ; Binding Sites ; Cell Line ; Chalcones/chemistry/*pharmacology ; Cyclooxygenase 2/metabolism ; I-kappa B Kinase/metabolism ; Inflammation/*drug therapy ; Interleukin-1beta/metabolism ; Lipopolysaccharides/immunology ; Microglia/*drug effects/immunology/metabolism ; Molecular Dynamics Simulation ; NF-kappa B/*antagonists & inhibitors ; Nitric Oxide Synthase Type II/metabolism ; Phosphorylation/drug effects ; Protein Binding ; Proto-Oncogene Proteins c-akt/*antagonists & inhibitors ; Rats ; Signal Transduction ; Toll-Like Receptor 4/*antagonists & inhibitors/metabolism ; Transcription Factor RelA/metabolism

OBJECTIVETo study the expression of stromal cell derived factor-1(SDF-1) in the airway and to investigate the role of SDF-1 receptor antagonist AMD3100 intervention in rats with asthma.

METHODSThirty Sprague-Dawley rats were randomly divided into three groups: normal control and asthma with and without AMD3100 intervention. The rat model of asthma was prepared by aerosolized ovalbum (OVA) challenge. The AMD3100 intervention group was administered with AMD3100 of 50 μg 30 minutes before challenge every other day, for 10 times. The characteristic airway inflammation and alterations of airway structures were observed by hemetoxylin and eosin staining. The levels of interleukin 4 and interleukin 5 in whole lung homogenates were measured using ELISA. RT-PCR was used to evaluate the expression of SDF-1 mRNA in the lung.

RESULTSThe airway wall thickness in the untreated asthma group was greater than that in the control and the AMD3100 intervention groups (P<0.05). The levels of interleukin 4 and interleukin 5 in whole lung homogenates in the AMD3100 intervention group were lower than those in the untreated asthma group (P<0.05). The expression of SDF-1 mRNA in the untreated asthma group was higher than that in the control and the AMD3100 intervention groups (P<0.05).

CONCLUSIONSSDF-1 may be associated with airway inflammation and remodeling in rats with asthma. AMD3100 may reduce the airway inflammation and improve airway remodeling by inhibiting the bioactivity of SDF-1.

Animals ; Asthma ; drug therapy ; etiology ; metabolism ; Chemokine CXCL12 ; analysis ; antagonists & inhibitors ; genetics ; physiology ; Female ; Heterocyclic Compounds ; pharmacology ; Interleukin-4 ; analysis ; Interleukin-5 ; analysis ; Lung ; metabolism ; pathology ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Receptors, CXCR4 ; antagonists & inhibitors

OBJECTIVETo test the effect of recombinant interleukin-4 (IL-4) and recombinant osteoprotegerin (OPG) in suppressing bone resorption induced by polyethylene wear particles..

METHODSA cranial bone allograft was introduced into the air pouches induced on the back of BALB/c mice, followed by injection of 1 ml suspension of polyethylene particles into the pouches. The mouse models were then divided into 3 groups to receive injections of saline (control), IL-4 alone, or IL-4 and OPG into the pouches. The tissues were harvested 21 days after bone implantation for molecular and histological analyses.

RESULTSPolyethylene wear particles-stimulated inflammatory responses (increased cellular infiltration and IL-1 and TNF production) were markedly reduced by IL-4 treatment either alone or combined with OPG (P<0.05). Polyethylene particles significantly increased tartrate-resistant acid phosphatase (TRAP) staining and bone absorption of the implanted bone graft, and IL-4 treatment, either alone or combined with OPG, obviously reduced the osteolysis induced by polyethylene particles (P<0.05).

CONCLUSIONIL-4 offers protection against polyethylene wear debris-induced inflammation and bone resorption in this mouse model. IL-4 combined with OPG can be a feasible and effective therapeutic approach to the treatment and prevention of polyethylene wear debris-associated osteolysis and aseptic loosening of the prosthetic components.

Animals ; Bone Resorption ; chemically induced ; prevention & control ; Disease Models, Animal ; Female ; Interleukin-4 ; pharmacology ; Mice ; Mice, Inbred BALB C ; Orthopedic Fixation Devices ; adverse effects ; Osteolysis ; chemically induced ; prevention & control ; Osteoprotegerin ; pharmacology ; Polyethylene ; antagonists & inhibitors ; Recombinant Proteins ; pharmacology

Adrenergic beta-2 Receptor Agonists ; pharmacology ; Anti-Inflammatory Agents ; pharmacology ; Asthma ; drug therapy ; physiopathology ; Chloroquine ; pharmacology ; Humans ; Myocytes, Smooth Muscle ; cytology ; drug effects ; metabolism ; Quaternary Ammonium Compounds ; pharmacology ; Receptors, Adrenergic, beta-2 ; metabolism ; Receptors, G-Protein-Coupled ; agonists ; metabolism ; Receptors, Interleukin-4 ; antagonists & inhibitors ; metabolism ; Respiratory System ; drug effects ; metabolism ; physiopathology