Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mononuclear phagocytes play a major role in immune and inflammatory responses. Bacterial lipopolysaccharide (LPS) induces monocytes to express a variety of genes by activating the NF-kappaB/Rel transcription factor family. Recently, we have reported that the tumor necrosis factor and interleukin 1 signaling pathways activate two kinases, IKK1 and IKK2. Phosphorylation of the IkappaB cytoplasmic inhibitors, IkappaBalpha, IkappaBbeta, and IkappaBepsilon, by these kinases triggers proteolytic degradation and the release of NF-kappaB/Rel proteins into the nucleus. At present, the role of the IKKs in LPS signaling has not been investigated. Here, we report that LPS induces IKK activity in human monocytes and THP-1 monocytic cells. The kinetics of activation of kinase activity in monocytic cells are relatively slow with maximal activity observed at 60 min, which coincides with the degradation of IkappaBs and the nuclear translocation of NF-kappaB. In transfection experiments, overexpression of wild type IKK1, a dominant negative mutant IKK1 (K44M), or wild type IKK2 did not affect LPS-induced kappaB-dependent transcription in monocytic cells. In contrast, a dominant negative mutant of IKK2 inhibited LPS induction of kappaB-dependent transcription in a dose-dependent manner. These results indicate that LPS induction of kappaB-dependent gene expression in human monocytic cells requires activation of IKK2.
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PMID:Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. 980 6

Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappaB. This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2). The kinetics of IKKalpha and IKKbeta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappaB: IkappaBalpha, IkappaBbeta, and IkappaBepsilon. Moreover, LPS activates IKKbeta preferentially, relative to IKKalpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.
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PMID:IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. 1047 96

Interleukin-10 (IL-10) has potent immunoregulatory effects on the maturation and the antigen-presenting cell (APC) function of dendritic cells (DCs). The molecular basis underlying these effects in DCs, however, is ill defined. It is well established that the transcription factor NF-kappaB is a key regulator of DC development, maturation, and APC function. This study was initiated to determine the effects of IL-10 on the NF-kappaB signaling pathway in immature DCs. IL-10 pretreatment of myeloid DCs cultured from bone marrow resulted in reduced DNA binding and nuclear translocation of NF-kappaB after anti-CD40 antibody or lipopolysaccharide (LPS) stimulation. Furthermore, inhibited NF-kappaB activation was characterized by reduced degradation, phosphorylation, or both of IkappaBalpha and IkappaBepsilon but not IkappaBbeta and by reduced phosphorylation of Ser536, located in the trans-activation domain of p65. Notably, IL-10-mediated inhibition of NF-kappaB coincided with suppressed IkappaB kinase (IKK) activity in vitro. Furthermore, IL-10 blocked inducible Akt phosphorylation, and inhibitors of phosphatidylinositol 3-kinase (PI3K) effectively suppressed the activation of Akt, IKK, and NF-kappaB. These findings demonstrate that IL-10 targets IKK activation in immature DCs and that suppressing the PI3K pathway in part mediates blockade of the pathway.
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PMID:Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity. 1511 57

Adjuvant-induced survival of T cells after antigen activation correlates with increased expression of Bcl-3. Bcl-3 is an NF-kappaB/IkappaB family member and has been implicated in transcriptional regulation in several cell types. We tested the ability of mice deficient in Bcl-3 (Bcl-3 KO) to exhibit T-cell adjuvant-induced survival after challenge with the superantigen staphylococcal enterotoxin B (SEB), using lipopolysaccharide (LPS) as a natural adjuvant. These studies showed that Bcl-3 is required for secondary gamma interferon (IFN-gamma) production by CD8 T cells but not for adjuvant-induced survival effects. Specifically, wild-type and Bcl-3 KO mice exhibited comparable long-term increases in the Vbeta8(+) T-cell populations, indicating no lack of survival in response to adjuvant stimulation in the Bcl-3 KO activated T cells. Ectopic expression of the Bcl-3-related molecules IkappaBalpha, IkappaBbeta, and IkappaBepsilon in SEB-activated T cells increased survival during in vitro culture in the absence of adjuvant, suggesting that these IkappaB molecules could exert a survival function in antigen-activated T cells in place of Bcl-3. However, Vbeta8(+) CD8 T cells from SEB- plus LPS-treated Bcl-3 KO mice produced less IFN-gamma upon in vitro restimulation than Vbeta8(+) CD8 T cells from wild-type mice. Therefore, Bcl-3 plays a unique role in the regulation of IFN-gamma production in this model system.
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PMID:CD8 T cells require Bcl-3 for maximal gamma interferon production upon secondary exposure to antigen. 1679 Jul 93