Pet Induces IL 1 , TNF , MIF and IL 1 Ra Through the IKK / NF B Pathway (original) (raw)
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Journal of Leukocyte Biology
It is well known that bacterial lipopolysaccharide (LPS) induces the synthesis of tumor necrosis factor a (TNF-a) and other inflammatory cytokines by primary monocytes and macrophages and that the Thi lymphokines, interleukin-2 (IL-2) and interferon-rny (IFN-y), augment this response. We investigated the ability of IL-2 and IFN-to induce the production of TNF-a mRNA and protein independently of LPS and the modulation of this response by macrophage colony-stimulating factor (M-CSF) and IL-lO. We found that IL-2 and IFN-y were both able to induce the accumulation of TNF-a mRNA, albeit with slower kinetics than LPS, and that they acted a primary deficiency in TNF production.J. Leukoc.
Immunology, 2007
Heterotrimeric Gi proteins play a role in signalling activated by lipopolysaccharide (LPS), Staphylococcus aureus (SA) and group B streptococci (GBS), leading to production of inflammatory mediators. We hypothesized that genetic deletion of Gi proteins would alter cytokine and chemokine production induced by LPS, SA and GBS stimulation. LPS-induced, heat-killed SA-induced and heat-killed GBS-induced cytokine and chemokine production in peritoneal macrophages from wild-type (WT), Gαi2–/– or Gαi1/3–/– mice were investigated. LPS induced production of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10 and interferon-γ-inducible protein-10 (IP-10); SA induced TNF-α, and IL-1β production; and GBS induced TNF-α, IL-6, IL-1β, macrophage inflammatory protein-1α (MIP-1α) and keratinocyte chemoattract (KC) production were all decreased (P < 0·05) in Gαi2–/– or Gαi1/3–/– mice compared with WT mice. In contrast to the role of Gi proteins as a positive regulator of mediators, LPS-induced production of MIP-1α and granulocyte–macrophage colony-stimulating factor (GM-CSF) were increased in macrophages from Gαi1/3–/– mice, and SA-induced MIP-1α production was increased in both groups of Gαi protein-depleted mice. LPS-induced production of KC and IL-1β, SA-induced production of GM-CSF, KC and IP-10, and GBS-induced production of IL-10, GM-CSF and IP-10 were unchanged in macrophages from Gαi2–/– or Gαi1/3–/– mice compared with WT mice. These data suggest that Gi2 and Gi1/3 proteins are both involved and differentially regulate murine inflammatory cytokine and chemokine production in response to both LPS and Gram-positive microbial stimuli.
TNF-Α May Mediate Inflammasome Activation in the Absence of Bacterial Infection in More than One Way
PLoS ONE, 2013
Members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor family of proteins are key modulators of innate immunity regulating inflammation. To date, microbial pathogen-associated molecules and toxins have been identified as key triggers of activation of inflammasomes. However, recently, environmental, and neurodegenerative stimuli have been identified that lead to IL-1b release by means of inflammasomes. IL-1b plays a crucial role during brain inflammation, and caspase-1 appears to be a key modulator of IL-1b bioactivity and the consequent transcriptional regulation of gene expression within the brain during inflammation. We show here that exposure of a human neuroblastoma cell line (SK-N-MC cells) to TNF-a promotes ROS-mediated caspase-1 activation and IL-1b secretion. The involvement of NF-kB in the regulation of IL-1b synthesis is investigated through specific inhibition of this transcription factor. The effect of TNF-a was abolished in the presence of ROS inhibitors as NAC, or DPI. Remarkably, SK-N-MC cells do not respond to ATP stimulation in spite of P2X 7 R expression. These results provide a mechanism by which danger signals and particulate matter mediate inflammation via the inflammasome in the absence of microbial infection.
Journal of Leukocyte Biology, 2005
Phagocytes are well-known effectors of the innate immune system to produce proinflammatory cytokines and chemokines such as tumor necrosis factor ␣ (TNF-␣), interleukin (IL)-1, and IL-8 during infections. Here, we show that infection of monocytes with wild-type Escherichia coli K1, which causes meningitis in neonates, suppresses the production of cytokines and chemokines (TNF-␣, regulated on activation, normal T expressed and secreted, macrophage-inflammatory protein-1, IL-1, and
Macrophage inflammatory protein-1
The International Journal of Biochemistry & Cell Biology, 2004
Macrophage inflammatory protein (MIP)-1␣ was identified 15 years ago as the first of now four members of the MIP-1 CC chemokine subfamily. These proteins termed CCL3 (MIP-1␣), CCL4 (MIP-1), CCL9/10 (MIP-1␦), and CCL15 (MIP-1␥) according to the revised nomenclature for chemokines are produced by many cells, particularly macrophages, dendritic cells, and lymphocytes. MIP-1 proteins, which act via G-protein-coupled cell surface receptors (CCR1, 3, 5), e.g. expressed by lymphocytes and monocytes/macrophages (M ), are best known for their chemotactic and proinflammatory effects but can also promote homoeostasis. The encouraging results of preclinical studies in murine models of inflammation, i.e. asthma, arthritis, or multiple sclerosis, have led to the development of potent CCR3 and 5 antagonists, some of which are currently being tested in first clinical trials.
The Journal of Immunology
The host response to Gram-negative LPS is characterized by an influx of inflammatory cells into host tissues, which is mediated, in part, by localized production of chemokines. The expression and function of chemokines in vivo appears to be highly selective, though the molecular mechanisms responsible are not well understood. All CXC (IFN-␥-inducible protein (IP-10), macrophage inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein (MCP)-1, MCP-5, MIP-1␣, MIP-1, and RANTES) chemokine genes evaluated were sensitive to stimulation by LPS in vitro and in vivo. While IL-10 suppressed the expression of all LPS-induced chemokine genes evaluated in vitro, treatment with IFN-␥ selectively induced IP-10 and MCP-5 mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1␣, and MIP-1 mRNA and/or protein. Like the response to IFN-␥, LPS-mediated induction of IP-10 and MCP-5 was Stat1 dependent. Interestingly, only the IFN-␥-mediated suppression of LPS-induced KC gene expression was IFN regulatory factor-2 dependent. Treatment of mice with LPS in vivo also induced high levels of chemokine mRNA in the liver and lung, with a concomitant increase in circulating protein. Hepatic expression of MIP-1␣, MIP-1, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer cell-depleted mice, while IP-10, KC, MIP-2, and MCP-1 were unaffected or enhanced. These findings indicate that selective regulation of chemokine expression in vivo may result from differential response of macrophages to pro-and antiinflammatory stimuli and to cell type-specific patterns of stimulus sensitivity. Moreover, the data suggest that individual chemokine genes are differentially regulated in response to LPS, suggesting unique roles during the sepsis cascade.
Inflammation Research, 1989
Interleukin-1 (IL-1) is a putative mediator of inflammation released by activated macrophagesin vitro. The IL-1 release by rat macrophages collected either from exudates in pertussis-induced air pouches or from the peritoneum during adjuvant arthritis has been investigated. In air pouch inflammation LPS-stimulated macrophages collected from sensitized animals release more IL-1 than cells from control rats at day 6 after challenge. This enhanced IL-1 release parallels the extent of mononuclear cell migration in the inflammatory lesion. In adjuvant arthritis LPS-stimulated macrophages collected from sensitized animals release more IL-1 than cells from control rats at days 16 and 23 after adjuvant injection. The secondary inflammation in arthritic rats was statistically significant at days 16 to 28. These results indicate that during immunological inflammation macrophages either from the inflamed area or from a non-inflamed region release more IL-1 than control cells. This release parallels the extent of the inflammation and may be important in its pathogenesis.
Differential Regulation of Macrophage Interleukin-1 (IL-1), IL
Infection and immunity, 1999
The ability of innate immune cells to differentially respond to various bacterial components provides a mechanism by which the acquired immune response may be tailored to specific pathogens. The response of innate immune cells to bacterial components provides regulatory signals to cognate immune cells. These signals include secreted cytokines and costimulatory molecules, and to a large extent they determine the quantitative and qualitative nature of the immune response. In order to determine if innate immune cells can differentially respond to bacterial components, we compared the responses of macrophages to two bacterially derived molecules, cholera toxin (CT) and lipopolysaccharide (LPS). We found that CT and LPS differentially regulated the expression of interleukin-12 (IL-12) and CD80-CD86 but not that of IL-1. LPS and CT each induced IL-1 expression in macrophages, while only LPS induced IL-12 and only CT induced CD80-CD86. These differences were markedly potentiated in gamma interferon (IFN-␥)-treated macrophages, in which LPS potently induced IL-12 and CD80-CD86 expression. In contrast, IFN-␥ treatment had no effect on the expression of IL-1. These results define a molecular basis for the differential pathogenicities of bacterial toxins and are relevant to the design of vaccine adjuvants able to selectively induce desired types of immunity.