Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1beta, IL-18 and tumor necrosis factor-alpha, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (>700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1beta and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.
CARD Signaling Adaptor Proteins/metabolism ; Carrier Proteins/metabolism/physiology ; Caspase 1/metabolism ; Humans ; Inflammasomes/*metabolism ; Inflammatory Bowel Diseases/metabolism/*pathology ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; Signal Transduction

T helper (Th) 17 cells are a kind of Th cell subset, and are distinct from the Th1 and Th2 cells and produce interleukin-17A (IL-17A, IL-17). Th17 cells have a mechanism of independent differentiation and developmental regulation. The differentiation and cytokine secretion of Th17 cells are regulated by TGF-β, IL-6, IL-23 and orphan nuclear receptor (RORγt). IL-17A induces pro-inflammatory cytokines and chemokines, mediating neutrophil recruitment. Increasing evidence implicated involvement of Th17 cells in anti-glomerular basement membrane disease, lupus nephritis and pauciimmune glomerulonephritis. In this review, we discussed the discovery of Th17 subset, its properties, its relationship with other Th subsets and involvement of Th17 cells in glomerulonephritis.
Animals ; Glomerulonephritis ; immunology ; Humans ; Interleukin-17 ; metabolism ; physiology ; Interleukin-23 Subunit p19 ; physiology ; Interleukin-6 ; physiology ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; physiology ; Th17 Cells ; immunology ; metabolism ; Transforming Growth Factor beta ; physiology

Inflammasomes are large multi-protein complexes that serve as a platform for caspase-1 activation, and this process induces subsequent maturation and secretion of the proinflammatory cytokines IL-1β and IL-18, as well as pyroptosis. As an important component of the innate immune system, early activation of inflammasomes in a variety of immune cell subsets can mediate inflammatory response and immunological conditions after burn injury. Here, we review the current knowledge of inflammasomes and its role in immunological and inflammatory response at the early stage of burn injury.
Apoptosis ; Burns ; immunology ; Caspase 1 ; metabolism ; Cytokines ; Humans ; Inflammasomes ; physiology ; Inflammation Mediators ; immunology ; Interleukin-18 ; immunology ; physiology ; Interleukin-1beta ; immunology ; physiology

The effect of a secretory proteinase from the pathogenic amoebae Acanthamoeba castellanii on hosts defense-oriented or regulatory proteins such as immunoglobulins, interleukin-1, and protease inhibitors was investigated. The enzyme was found to degrade secretory immunoglobulin A (sIgA), IgG, and IgM. It also degraded interleukin-1alpha (IL-1alpha) and IL-1beta. Its activity was not inhibited by endogenous protease inhibitors, such as alpha2-macroglobulin, alpha1-trypsin inhibitor, and alpha2-antiplasmin. Furthermore, the enzyme rapidly degraded those endogenous protease inhibitors as well. The degradation of hosts defense-oriented or regulatory proteins by the Acanthamoeba proteinase suggested that the enzyme might be an important virulence factor in the pathogenesis of Acanthamoeba infection.
Acanthamoeba/*enzymology/pathogenicity ; Animals ; Endopeptidases/*physiology ; Immunoglobulins/*metabolism ; Interleukin-1/*metabolism ; Protease Inhibitors/*metabolism ; Support, Non-U.S. Gov't ; Virulence

BACKGROUND/AIMS: Saccharomyces boulardii (S. boulardii) has been reported to be beneficial in the treatment of inflammatory bowel disease, however, little is known about its mechanism of action. Peroxisome proliferator- activated receptor-gamma (PPAR-gamma) is recently found to regulate inflammation in intestinal epithelial cells. We hypothesized that the anti-inflammatory effects of S. boulardii are mediated, in part, through PPAR-gamma. To test this hypothesis, we examined the ability of S. boulardii to modulate the expression of PPAR-gamma in human colon cells. METHODS: Effects of S. boulardii on survival and proliferation of HT-29 human colon cells were assessed by MTT and [3H]thymidine incorporation assays. PPAR-gamma expression was assessed by Western blot and RT-PCR. Induction of interleukin-8 (IL-8) expression by tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), or lipopolysaccharide (LPS) was assessed by RT-PCR. RESULTS: S. boulardii did not affect viability and proliferation of HT-29 cells. S. boulardii up-regulated PPAR-gamma expression at both mRNA and protein levels. Pretreatment of HT-29 cells with S. boulardii blocked PPAR-gamma down-regulation by TNF-alpha, IL-1beta, or LPS, whereas it ameliorated IL-8 response to these proinflammatory factors. CONCLUSIONS: S. boulardii stimulates PPAR-gamma expression and reduces response of human colon cells to proinflammatory cytokines.
Cell Proliferation ; Colon/*metabolism ; *Gene Expression ; HT29 Cells ; Humans ; Interleukin-1/metabolism ; Interleukin-8/metabolism ; Lipopolysaccharides/pharmacology ; PPAR gamma/genetics/*metabolism ; Saccharomyces/*physiology

OBJECTIVE: To evaluate the effect of biglycan on the signaling of cytokines (epidermal growth factor, osteogenic protein-1, and interleukin-1) in bovine intervertebral disc cells. METHODS: Nucleoplasty (NP) and annulus fibrosus (AF) cells of the intervertebral disc tissues were isolated from the tails of young adult bovine. First, the cells were treated in 3 ways: Biglycan alone, cytokines alone (epidermal growth factor, osteogenic protein-1, or interleukin-1), and biglycan combined with cytonkines. Western blot was used to observe the singling of biglycan and cytokines in bovine intervertebral disc cells, and to identify the effect of biglycan on cytokines mentioned above. RESULTS: Biglycan upregulated the signaling (3- 4 folds) with the optimal effect at 10 min and 20 μmol/L both in the AF cells and NP cells. Epidermal growth factor, osteogenic protein-1, or interleukin-1 also upregulated the protein expression in the extracellular matrix of intervertebral disc cells. When combined different biglycan concentrations with epidermal growth factor, osteogenic protein-1, or interleukin-1 to treat the intervertebral disc cells, the concentration of biglycan rose, whereas the cytokine signal decreased both in the bovine AF and NP cells (P<0.01). There was no significant difference between the AF and NP cells. CONCLUSION Biglycan can adhere to the intervertebral disc cells to activate the extracellular signal-regulated kinase (ERK) pathway and this effect is time and concentration dependent. Byglycan can decrease not only the anabolism effect of epidermal growth factor and osteogenic protein-1, but also the catabolism effect of interleukin-1. This regulatory role of biglycan may be very important to maintain the metabolism balance. Biglycan may be good for the repair of intervertebral disc.
Animals ; Biglycan ; physiology ; Bone Morphogenetic Protein 7 ; metabolism ; physiology ; Cattle ; Cells, Cultured ; Cytokines ; metabolism ; physiology ; Epidermal Growth Factor ; metabolism ; physiology ; Interleukin-1 ; metabolism ; physiology ; Intervertebral Disc ; cytology ; metabolism ; Signal Transduction

OBJECTIVETo explore the biological effect of Notch ligand Delta-1 (Notch L delta-1) on the sIL-6R during the differentiation of erythroid hematopoiesis.

METHODSMononuclear cells (MNCs) was isolated from the normal cord blood using Ficoll graduation solution. MNCs were enriched for CD34(+) CD38(-) cells by CD34 immunomagnetic beads and a FACS Vantage. CD34(+) CD38(-) cells was cultured for 7 days in the presence of SCF, Flt3L, TPO and IL-3 (4GFs). The cultured cells was detected for the expression of IL-6R and GPA. The subsequently enriched CD36(+) erythroid progenitors were sorted for cells with IL-6R(+) and IL-6R(-) using FACS Vantage. The CD36(+) GPA(-) IL-6R(-) cells were respectively cultured in the 4GFs, 4GFs + IL-6 or 4GFs + FP6 containing medium in the presence or absence of Notch L delta-1 for 14 days and CD36(+) GPA high red cells were counted.

RESULTSIL-6R cells accounted for 95% of CD36(+) GPA(+) cells. The CD36(+) GPA(-) cells was clearly divided into IL-6R(+) (46%) and IL-6R(-) (54%) subpopulations, the IL-6R(+) cell subpopulation formed only a few GM colonies (2.1 +/- 1.8) and a greater number of BFU-E colonies were generated from the IL-6R(-) subpopulation (58.2 +/- 18.1) (P < 0.05). The number of CD36(+) GPA high cell was (1.400 +/- 0.180) x 10(6) in the presence of FP6, lower than that [(2.460 +/- 0.190) x 10(6)] in the presence of FP6 + Notch L delta-1 (P < 0.05).

CONCLUSIONNotch L delta-1 enhances the sIL-6R-mediated effects of IL-6 on the generation of erythroid cells.

ADP-ribosyl Cyclase 1 ; Antigens, CD34 ; Cell Differentiation ; drug effects ; physiology ; Cells, Cultured ; Erythroid Precursor Cells ; cytology ; drug effects ; Humans ; Interleukin-6 ; metabolism ; physiology ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; pharmacology ; Receptors, Interleukin-6 ; metabolism ; physiology

Nitric oxide (NO) has been considered as an important mediator in inflammatory phases and in loss of cartilage. In inflammatory arthritis, NO levels are correlated with disease activity and articular cartilage is able to produce large amounts of NO with the appropriate inducing factor such as cytokines. The old animals are shown to have a greater sensitivity to NO than young animals. This study evaluated the basal production of NO in normal and OA-affected chondroyctes from young and old patients and compared the levels of NO formation in response to IL-1beta. The results showed that the basal levels were 7-fold higher in old chondrocytes than those of young cells. However, the IL-1beta induced NO production was seen to decrease with age. Aminoguianidine (AG), a competitive inhibitor of iNOS, inhibited NO formation completely in both chondrocytes from young and old individuals. However, at the same concentration of AG it caused partial inhibition of NO and iNOS formation in chondrocytes from OA-affected individuals. In addition, although the IL-1beta induced NO production was much lesser than that of young chondrocytes, the inhibition of collagen production by IL-1beta was prominent in old chondrocytes and OA-affected chondrocytes. These results suggest that age-related differences in the regulation of NO production and collagen production, which may affect the ageing cells and osteoarthritic changes in some way.
Aging/*physiology ; Cartilage, Articular/*physiopathology ; Cells, Cultured ; Chondrocytes/*metabolism ; Collagen Type II/metabolism ; Enzyme Inhibitors/pharmacology ; Guanidines/pharmacology ; Human ; Interleukin-1/pharmacology ; Nitric Oxide/*biosynthesis ; Osteoarthritis/*metabolism

Nitric oxide (NO) has been considered as an important mediator in inflammatory phases and in loss of cartilage. In inflammatory arthritis, NO levels are correlated with disease activity and articular cartilage is able to produce large amounts of NO with the appropriate inducing factor such as cytokines. The old animals are shown to have a greater sensitivity to NO than young animals. This study evaluated the basal production of NO in normal and OA-affected chondroyctes from young and old patients and compared the levels of NO formation in response to IL-1beta. The results showed that the basal levels were 7-fold higher in old chondrocytes than those of young cells. However, the IL-1beta induced NO production was seen to decrease with age. Aminoguianidine (AG), a competitive inhibitor of iNOS, inhibited NO formation completely in both chondrocytes from young and old individuals. However, at the same concentration of AG it caused partial inhibition of NO and iNOS formation in chondrocytes from OA-affected individuals. In addition, although the IL-1beta induced NO production was much lesser than that of young chondrocytes, the inhibition of collagen production by IL-1beta was prominent in old chondrocytes and OA-affected chondrocytes. These results suggest that age-related differences in the regulation of NO production and collagen production, which may affect the ageing cells and osteoarthritic changes in some way.
Aging/*physiology ; Cartilage, Articular/*physiopathology ; Cells, Cultured ; Chondrocytes/*metabolism ; Collagen Type II/metabolism ; Enzyme Inhibitors/pharmacology ; Guanidines/pharmacology ; Human ; Interleukin-1/pharmacology ; Nitric Oxide/*biosynthesis ; Osteoarthritis/*metabolism

OBJECTIVETo investigate the changes in plasma level of interleukin-13 (IL-13) and the changes in the pulmonary IL-13 mRNA content and the pulmonary activator protein-1 (AP-1) activity of the rats inflicted with acute lung injury (ALI) induced by lipopolysaccharide (LPS), so as to explore the relationship between IL-13 expression and AP-1 activity.

METHODSOne hundred and twenty Wistar rats were employed in the study and were randomly divided into A (2 mg/kg), B (4 mg/kg), C (6 mg/kg) and D (8 mg/kg) groups according to different dosage of LPS administration and a control group (NS group) at each observing time point. The rats were observed at 1, 2, 4 and 6 postburn hours (PBHs) and every 6 rats were deployed in every group and each time points. A model of systemic inflammatory response syndrome-acute lung injury (SIRS-ALI) was replicated in Wistar rats. The plasma content of IL-13 was assayed by enzyme-linked immunosorbent assay (ELISA), and the pulmonary tissue content of IL-13 mRNA and AP-1 activity by reverse transcriptase-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assays (EMSA).

RESULTSThe plasma content of IL-13, pulmonary content of IL-13 mRNA and AP-1 activity increased simultaneously after LPS administration. All the above indices were significantly different statistically between the LPS groups and the control group (P < 0.05 - 0.01). The plasma level of IL-13 and pulmonary tissue mRNA content and AP-1 activity in A, B, C and D groups were increased significantly with peak levels at 2 PBHs.

CONCLUSIONThe pulmonary AP-1 activity increased with the enhanced expression of IL-13, which was related to the development of SIRS-ALI.

Acute Lung Injury ; metabolism ; Animals ; Endotoxins ; toxicity ; Female ; Interleukin-13 ; blood ; genetics ; physiology ; Lung ; chemistry ; Male ; Rats ; Rats, Wistar ; Transcription Factor AP-1 ; analysis ; physiology