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)

The murine B-cell lymphoma CH12, like many other murine cells, expresses intracisternal A-type particles (IAPs). When CH12 cells are treated with lipopolysaccharide, the cells differentiate and secrete immunoglobulin M. The expression of IAP genes was also increased, in parallel with the increased expression of immunoglobulin genes. The amount of IAP mRNA increased within 48 h of lipopolysaccharide treatment and reached a level fivefold higher than that in unactivated CH12 cells. The two major IAP transcripts (7.2 and 5.4 kilobases) were induced to similar extents. The increased level of mRNA was reflected in higher levels of the major IAP structural protein p70, whose abundance increased 3.6-fold. The number of IAP particles per cell also increased upon activation of CH12, from 67 in nonsecreting CH12 to 290 in secreting cells. All of the IAPs were confined to the cisternae of the endoplasmic reticulum (ER), regardless of the differentiation state of the cell. Accompanying the induction of p70 was the induction of the related IAP polypeptide p102. A third viral polypeptide, p120, was also made in CH12; its abundance was almost unchanged. Localization of the IAP proteins on ultrathin frozen sections showed that most were assembled into particles in the ER. However, there were small pools of unassembled proteins both in the ER and on the plasma membrane. p70 and p120 could be detected, by iodination, on the surfaces of both secreting and nonsecreting CH12 cells. Unlike p70 and p120, p102 did not seem to be membrane associated. Taken together, these observations show that IAP expression is regulated developmentally in B lymphocytes. Also, these observations point to possible interactions between IAP genes and other cellular genes.
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PMID:Expression of intracisternal A-type particles is increased when a B-cell lymphoma differentiates into an immunoglobulin-secreting cell. 249 59

The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.
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PMID:Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. 783 10

Human polymorphonuclear leukocytes (PMN) stimulated by lipopolysaccharide (LPS) produce interleukin-12 (IL-12). Both the free IL-12 p40 chain and minute amounts of the biologically active IL-12 p70 heterodimers are produced by PMN. Interferon-gamma (IFN-gamma) enhanced the LPS-induced secretion of both the free IL-12 p40 chain and the p70 heterodimer by approximately fivefold. As observed for other IL-12-producing cell types, the ratio of free p40 chain to p70 heterodimer secreted by LPS-stimulated PMN was approximately 20:1. LPS induced a 100-fold increase of IL-12 p40 mRNA, but had minimal effect on p35 mRNA accumulation. IFN-gamma enhanced the LPS-induced accumulation of p40 mRNA and directly induced a several-fold increase in the accumulation of p35 mRNA. Therefore, the combined effect of LPS and IFN-gamma induced sufficient expression of both p40 and p35 to attain production of the biologically active p70 heterodimer at physiologically relevant concentrations. The ratio between p40 and p35 mRNA abundance in PMN stimulated with both LPS and IFN-gamma was approximately 200:1, explaining the secretion of the free p40 chain in much higher concentrations than the p70 heterodimer. IL-10, an inhibitor of the production of various cytokines in PMN, also suppressed IL-12 mRNA accumulation and secretion by PMN. Because of the important immunoregulatory function of IL-12, in particular induction of IFN-gamma production and facilitation of T helper cell type 1 response, the ability of PMN to produce IL-12 suggests that neutrophils may play an active role in the regulatory interaction between innate resistance and adaptive immunity.
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PMID:Interleukin-12 production by human polymorphonuclear leukocytes. 784 18

Gamma interferon (IFN-gamma) is produced in response to circulating lipopolysaccharide (LPS) and contributes to the lethality of endotoxic shock. To address the cellular source of IFN-gamma production in vivo, T cells and B cells were magnetically purified from C57BL/6 mouse spleens 5 h following endotoxin injection. IFN-gamma RNA was abundant in splenic CD4+ and CD8+ T cells and in a T- and B-cell-depleted population of splenocytes containing 34% NK1.1+ natural killer (NK) cells. Because interleukin 12 (IL-12) is a known inducer of IFN-gamma synthesis by cultured T cells and NK cells, we examined whether IL-12 might be involved in IFN-gamma release during endotoxemia. mRNA encoding the p40 subunit of IL-12 increased markedly in the spleens of C57BL/6 mice at 2 h after LPS injection, whereas p35 IL-12 mRNA was constitutively expressed at all times. Bioactive IL-12 (p70 heterodimer) was detected in mouse serum at 2 to 4 h after LPS injection. Similar results were obtained using a p40 subunit-specific enzyme-linked immunosorbent assay. Endotoxin-insensitive C3H/HeJ mice generated threefold less IL-12 p70 and IFN-gamma at these times than endotoxin-sensitive C3H/HeOuJ mice. Pretreatment of mice with polyclonal anti-mouse IL-12 antibody reduced IFN-gamma levels present at 6 h post-LPS nearly sixfold in three separate experiments. These studies support a role for IL-12 as a proximal stimulator of IFN-gamma release during endotoxemia.
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PMID:Interleukin 12 is produced in vivo during endotoxemia and stimulates synthesis of gamma interferon. 792 80

Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon gamma (IFN-gamma) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor alpha (TNF-alpha), IL-1 and also IFN-gamma from lymphocytes acting at the level of accessory cells. Because TNF-alpha and IL-1 are not efficient inducers of IFN-gamma, the mechanism by which IL-10 inhibits IFN-gamma production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL-10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-gamma both in vitro and in vivo, the mechanism of inhibition of IFN-gamma by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-gamma production induced by NKSF/IL-12, and also, the IFN-gamma production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-alpha, or IL-1 beta can significantly inhibit IFN-gamma production in response to various stimuli and that NKSF/IL-12 and IL-1 beta can overcome the IL-10-mediated inhibition of IFN-gamma, suggest that IL-10 inhibition of IFN-gamma production is primarily due to its blocking production from accessory cells of the IFN-gamma-inducer NKSF/IL-12, as well as the costimulating molecule IL-1 beta.
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PMID:Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. 810 88

Interleukin-12 (IL-12) is a key inducer of differentiation of uncommitted T helper (TH) cells toward the TH1 phenotype, which regulates cellular immunity, whereas IL-10 inhibits TH1 functions and potentiates TH2-regulated responses (i.e., humoral immunity). To examine the potential effects of stress on TH1/TH2 balance, we studied the ability of three prototype stress hormones-dexamethasone (a synthetic glucocorticoid) and the catecholamines norepinephrine and epinephrine-to alter the production of IL-12 (p70) and IL-10 induced by bacterial lipopolysaccharide (LPS) in human whole blood. Dexamethasone inhibited LPS-induced bioactive IL-12 production in a dose-dependent fashion and at physiologically relevant concentrations; it had no effect on IL-10 secretion. The glucocorticoid-induced reduction of IL-12 production was antagonized by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was mediated by the glucocorticoid receptor. Norepinephrine and epinephrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations; both catecholamines, however, dose-dependently increased the production of IL-10. The effects of either catecholamine on IL-12 or IL-10 secretion were blocked completely by propranolol, a beta-adrenoreceptor antagonist, indicating that they were mediated by the beta-adrenergic receptor. These findings suggest that the central nervous system may regulate IL-12 and IL-10 secretion and, hence, TH1/TH2 balance via the peripheral end-effectors of the stress system. Thus, stress may cause a selective suppression of TH1 functions and a shift toward a TH2 cytokine pattern rather than generalized TH suppression. The TH1-to-TH2 shift may be responsible for the stress-induced susceptibility of the organism to certain infections. Through the same or a reciprocal mechanism, states associated with chronic hyperactivity or hypoactivity of the stress system might influence the susceptibility of an individual to certain autoimmune, allergic, infectious, or neoplastic diseases.
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PMID:Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. 890 82

The role of interleukin-12 (IL-12) in Th1 cell differentiation is well established. The heterodimer p70, composed of a p40 and a p35 chain, is the biologically active form. IL-12 production by human monocytes is enhanced by interferon-gamma (IFN-gamma) and inhibited by IL-10 and prostaglandin E2 (PGE2). Peripheral blood mononuclear cells from human immunodeficiency virus (HIV)-infected individuals reportedly have impaired IL-12 p40 and p70 production on stimulation with Staphylococcus aureus Cowan I (SAC) in vitro. Both PGE2 and IL-10 previously were proposed to be instrumental in this defect in IL-12 production. Here, we studied IL-12 p40 and p70 production in relation to IL-10 and PGE2 production in whole blood cultures from HIV-infected individuals. On stimulation with lipopolysaccharide, IL-12 production was normal. However, on stimulation with SAC, IL-12 p40 and p70 production was decreased in HIV-infected individuals and correlated significantly with decreased peripheral blood CD4+ T-cell number and T-cell reactivity to CD3 monoclonal antibody in vitro. However, IL-10 and PGE2 production in cultures from HIV-infected individuals was normal and did not relate to IL-12 production. In conclusion, IL-12 production by cells from HIV-infected individuals is impaired under certain conditions in vitro and this decrease is independent of IL-10 or PGE2 production.
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PMID:Interleukin-12 (IL-12) production in whole blood cultures from human immunodeficiency virus-infected individuals studied in relation to IL-10 and prostaglandin E2 production. 900 60

Interferon (IFN)-alpha/beta-mediated negative regulation of interleukin 12 (IL-12) and IFN-gamma proteins is reported here. Both IFN-alpha and IFN-beta inhibited fixed Staphylococcus aureus Cowan strain induction of IL-12 and IFN-gamma production by mouse splenic leukocytes in culture. Extended studies with IFN-alpha demonstrated that inhibition was at the level of biologically active IL-12 p70. Effects were selective, as induction of tumor necrosis factor was unaffected and induction of IL-6 was enhanced. Neutralization of IFN-alpha/beta expressed endogenously during infections with murine cytomegalovirus (MCMV) enhanced early IL-12 and IFN-gamma protein production. Furthermore, during infections of mice with lymphocytic choriomeningitis virus (LCMV), this treatment revealed a previously undetected early IL-12 and IFN-gamma protein expression, and mice deficient in IFN-alpha/beta receptor function, but not control mice, also expressed endogenous LCMV-induced IL-12. The effects of IFN-alpha/beta neutralization on production of IL-12 and IFN-gamma during the viral infections were detected in both serum samples and medium conditioned with splenic leukocytes isolated from infected animals. In vitro studies demonstrated that splenic leukocytes isolated from LCMV-infected mice were primed to produce IL-12 in response to stimulation with Staphylococcus aureus Cowan strain, but that this responsiveness was sensitive to added IFN-alpha. Moreover, endogenous IFN-alpha/beta induced by LCMV inhibited in vivo lipopolysaccharide stimulation of IL-12 production. These results demonstrate a new pathway for regulating cytokine responses, and suggest a mechanism for inhibition of IL-12-dependent immune responses during viral infections.
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PMID:Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. 901 36

Interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) exert protective effects during experimental endotoxemia through upregulation of cellular immunity and phagocytic functions. They are part of a positive regulatory feedback loop that enhances the production of the other. Because critically ill patients show a marked suppression of T-cell and macrophage functions with a high susceptibility to infection, potential defects in the immunity/inflammation upregulating IL-12 IFN-gamma pathway were studied. As an ex vivo model of endotoxemia, lipopolysaccharide (LPS) stimulated whole blood from 25 critically ill patients and 12 healthy individuals was incubated with either recombinant human (rh) IL-12 or rhIFN-gamma, respectively. IFN-gamma dose-dependently (P < .05) increased the release of IL-12 p40 and p70 into LPS-stimulated whole blood from healthy humans without effect in whole blood from critically ill patients. RhIL-12 p70 enhanced (P < .05) the secretion of IFN-gamma in controls, while it was ineffective in LPS-stimulated whole blood from critically ill patients. The observed inhibition of the IL-12 IFN-gamma pathway is not specific to LPS, since Staphylococcus aureus Cowan strain I (SAC)-stimulated whole blood from critically ill patients showed similar suppression. The secretion of IL-12 and IFN-gamma was less reduced in critically ill patients when using isolated cultures of adherent cells or lymphocytes. Although preculture of whole blood from healthy humans with IL-10, but not with IL-4, mimicked suppression of the IL-12 IFN-gamma pathway similar to that observed during critical illness, the release of antiinflammatory reacting cytokines (IL-4, IL-10, transforming growth factor [TGF]-beta 1) was decreased into LPS-stimulated whole blood from critically ill patients. These results indicate at least two mechanisms responsible for dramatic disturbances of the IL-12 IFN-gamma pathway during critical illness: (1) deactivation of IL-12 and IFN-gamma producing leukocytes in vivo early after the primary insult, and (2) presence of serum suppressive factors different from IL-4, IL-10, or TGF-beta 1. Because IL-12 and IFN-gamma upregulate essential immune functions, the marked inhibition of IL-12 and IFN-gamma release may be pivotal for high susceptibility of critically ill patients to infection.
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PMID:Inhibition of the defense system stimulating interleukin-12 interferon-gamma pathway during critical Illness. 905 43

Dendritic cells (DC) are important initiators of specific primary immune responses because they are the only APC that can efficiently activate naive Th cells. DC have the capacity to produce interleukin-12 (IL-12), a cytokine that plays a pivotal role in the development of Th1-mediated cellular immune responses. The present study focuses on the conditions under which human DC produce bioactive IL-12 p70 and, consequently, direct the development of naive T helper (Th) cells toward the Th1 phenotype. Bacteria or bacterial compounds such as Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS) induced substantial IL-12 levels in DC, which could be further upregulated by interferon-gamma (IFN-gamma), whereas induction of IL-12 production via CD40 ligation required IFN-gamma as an obligatory, complementary signal. Also, activated naive Th cells were poor inducers of IL-12 production, unless exogenous IFN-gamma was present, whereas activated memory Th cells were effective inducers of IL-12 production and did not require exogenous IFN-gamma. Next, the cytokine profiles of matured Th cells that were primed by DC under different conditions were examined. DC promoted the development of naive Th cells into memory Th0 cells that produced both the type 1 cytokine IFN-gamma and the type 2 cytokine IL-4. In contrast, after activation with SAC, DC efficiently directed the development of Th1 cells through the release of IL-12. An APC-independent Th cell maturation model, using either recombinant IL-12 or supernatants of SAC-activated DC and neutralizing anti-IL-12 antibodies, confirmed that DC-derived IL-12 was the major Th1 skewing factor. Together, these data indicate that the contact between DC and naive Th cells during the initiation of specific immune responses does not result in the efficient induction of IL-12 production and that, consequently, exogenous IL-12-inducing factors are required to promote primary Th1-mediated cellular immune responses.
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PMID:Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. 929 25


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