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

Combinations of delta 9-tetrahydrocannabinol (delta 9-THC) and bacterial endotoxin were shown to be hyperadditively toxic for mice. A variety of purified lipopolysaccharide (LPS) preparations elicted enhanced mortality in combination with delta 9-THC. Escherichia coli O26:B6 LPS (Boivin preparation) at an essentially nonlethal dose of 2.5 mg/kg reduced the dose of delta 9-THC required to kill 50% of the treated mice from ca. 350 to 150 mg/kg. Inbred BALB, DBA, and C3H/HeCr mice, noninbred ICR mice, and hybrid CDF1 and BDF1 mice were hyperreactive to combinations of delta 9-THC and LPS. Moreover, a variety of heat-killed intestinal and gram-negative bacteria, live E. coli, and complexes of lipid A with a variety of proteins substituted for LPS in the synergistic toxicity of LPS and delta 9-THC. Extracts of marijuana also elicited hyperreactivity to LPS. The hyperadditive lethality of combinations of delta 9-THC and LPS was markedly less in mice rendered refractory to LPS or delta 9-THC by repeated administration of LPS or delta 9-THC, respectively.
 ...
PMID:Enhanced susceptibility of mice to combinations of delta 9-tetrahydrocannabinol and live or killed gram-negative bacteria. 33 Apr 5

Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, has been reported to be suppressive on some immune functions. Since interferons (IFNs) are important immunomodulatory proteins, the effect of in vivo or in vitro administration of THC on induction of IFN by various mitogens was examined. Splenocytes from normal mice in the presence of THC produced significantly less IFN when stimulated by phytohemagglutinin (PHA), concanavalin A (Con A), or Escherichia coli lipopolysaccharide (LPS). Induction of IFN by a bacterial antigen, Legionella pneumophila bacterial cells, was also suppressed by THC. Also, splenocytes which were incubated up to 24 h in the presence of THC partially recovered responses to mitogens when cells were washed before stimulation. This suggested that THC must be present in order to mitigate IFN induction. Splenocyte cultures from mice which were chronically injected with THC for 6-8 weeks were also less responsive to induction of IFN by the various mitogens. These results suggest that at least part of the immunosuppressive effects of THC may be related to depressed IFN production by stimulated lymphocytes. Since Con A and PHA are T cell mitogens and LPS is considered to be a macrophage and B cell stimulator, suppression of IFN production by these classes of cells indicate a wide range of effects of THC.
 ...
PMID:In vitro and in vivo suppressive effects of delta-9-tetrahydrocannabinol on interferon production by murine spleen cells. 243 Sep 4

The objective of this study was to determine the effect of delta-9-tetrahydrocannabinol (delta-9-THC), the major psychoactive component of marihuana, on macrophage protein expression in response to bacterial immunomodulators. Peritoneal macrophages of (B6C3)F1 mice receiving Propionibacterium acnes exhibited a novel protein profile when compared to resident or vehicle-treated macrophages. In contrast, macrophages from mice treated with P. acnes in concert with delta-9-THC exhibited profiles for which the majority of protein species reverted to patterns seen in profiles of resident or vehicle-treated macrophages. Treatment of the murine macrophage line P388D1 (DBA/2) in vitro with bacterial lipopolysaccharide (LPS) resulted in the hyperproduction of a subset of proteins ranging from 73 to 18 kD relative molecular weight. Coexposure of the P388D1 cells to LPS and 10(-7) M to 10(-5) M delta-9-THC resulted in a dose-related depletion of these proteins. These results suggest that delta-9-THC suppresses the expression of proteins elicited by macrophage bacterial immunomodulators.
 ...
PMID:Delta-9-tetrahydrocannabinol inhibits macrophage protein expression in response to bacterial immunomodulators. 253 3

We have previously observed that delta 9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, increased supernatant interleukin-1 (IL-1) bioactivity in cultures of mouse resident peritoneal macrophages stimulated with lipopolysaccharide (LPS). In this study, experiments were performed to determine whether THC treatment similarly affected phagocytes of human origin. The results showed that THC increased the levels of supernatant IL-1 bioactivity of two human monocytic cell lines, but only if the cells were differentiated with phorbol myristate acetate. Undifferentiated cells displayed decreased IL-1 bioactivity in response to THC. However, under conditions in which THC augmented supernatant IL-1 bioactivity from THP-1 cells, ELISA studies showed that the levels of IL-1 alpha and IL-1 beta were unchanged and decreased, respectively. Furthermore, supernatant interleukin-6 (IL-6) levels were decreased, but tumor necrosis factor (TNF-alpha) levels were increased by THC treatment. These results show that THC treatment modulates cytokine production and/or release by mouse and human macrophages and the drug effects on IL-1-like bioactivity in the supernatants of the human THP-1 cells are due to increased levels of other cytokines, such as TNF-alpha, rather than IL-1 itself.
 ...
PMID:delta 9-Tetrahydrocannabinol (THC) modulates IL-1 bioactivity in human monocyte/macrophage cell lines. 816 9

Macrophages have been shown to undergo a sequential process to full activation in response to priming and triggering signals such as gamma interferon (IFN gamma) and bacterial lipopolysaccharide (LPS). These cells also may be driven directly to full activation by exposure to relatively high concentrations of LPS. Each of the stages to activation is associated with differential protein expression suggesting that newly synthesized proteins are associated with the functional activities attributable to that activation state. These observations indicate that protein profiles may serve as a barometer of the macrophage activation state. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, was shown to inhibit inducible protein expression in response to the priming agents Concanavalin A (Con A) supernatant and IFN gamma. THC also suppressed protein expression in response to LPS. P388D1 and RAW264.7 macrophage-like cells, treated with Con A supernatant or IFN gamma, exhibited restructuring of protein profiles based on iso-Dalt two-dimensional gel electrophoresis. Protein profile restructuring, distinctive from that elicited in response to priming agents, was seen for macrophages treated with LPS. Treatment of macrophages with Con A supernatant, IFN gamma, or LPS in concert with THC (10(-7) M to 10(-5) M), resulted in the generation of protein profiles whose patterns reverted approximately to those of unprimed or unactivated macrophages. THC was shown to alter the expression of select proteins whose induction is associated with macrophage priming or activation. The expression of P388D1 macrophage class II Ia molecules of the major histocompatibility complex (MHC), in response to Con A supernatant and IFN gamma, was inhibited. THC also altered the expression of tumor necrosis factor alpha (TNF alpha) elicited by RAW264.7 cells in response to LPS. These results suggest that THC alters macrophage functional activities, at least in part, by suppressing their capacity to express effector molecules elicited in response to priming and activating signals.
 ...
PMID:Inhibition of macrophage inducible protein expression by delta-9-tetrahydrocannabinol. 819 97

Delta 9-tetrahydrocannabinol (delta 9-THC), the major psychoactive component of marijuana, has been shown to suppress macrophage soluble cytolytic activity. The purpose of this study was to determine whether delta 9-THC inhibited this function by affecting tumor necrosis factor-alpha (TNF-alpha). The RAW264.7 macrophage cell line was used as an in vitro bacterial lipopolysaccharide-inducible system for production of TNF-alpha. Macrophage-conditioned medium of RAW264.7 macrophages treated with delta 9-THC was shown to be deficient in tumoricidal activity. Immunoprecipitation experiments demonstrated that the macrophage-conditioned medium of cultures treated with drug contained lower levels of TNF-alpha. Northern analysis indicated that delta 9-THC had no effect on the levels of TNF-alpha messenger RNA. However, radiolabel pulsing and pulse-chase experiments revealed that the intracellular conversion of the 26-kD presecreted form of TNF-alpha to the 17-kD secreted form was inhibited by the drug. These results indicate that delta 9-THC suppresses soluble macrophage tumoricidal activity, at least in part, by decreasing the intracellular conversion of presecretory TNF-alpha to its 17-kD secretory form.
 ...
PMID:Delta 9-tetrahydrocannabinol inhibition of tumor necrosis factor-alpha: suppression of post-translational events. 826 18

The major psychoactive and immunosuppressive component of marihuana, delta 9-tetrahydrocannabinol (delta 9-THC), was investigated for its effects on primary humoral immune responses in the B6C3F1 mouse strain. Oral administration of 50-200 mg/kg delta 9-THC produced a selective and dose related inhibition of primary humoral immune responses to the T-cell dependent antigen, sRBC, as measured by the antibody forming cell (AFC) response with no inhibitory effect on humoral responses to the T-cell independent antigen, DNP-Ficoll. A similar profile of immune inhibition was observed following in vitro direct addition of delta 9-THC to naive spleen cell cultures sensitized with defined antigens. delta 9-THC produced a marked and dose related inhibition of the in vitro sRBC AFC response while having no inhibitory effects on T-cell independent responses to either DNP-Ficoll or the polyclonal B-cell activator, lipopolysaccharide. This selective inhibition of the sRBC response was not due to a shift in the peak day of response or a direct cytotoxic effect on spleen cells. In vivo kinetic studies demonstrated that inhibition by delta 9-THC of the sRBC response was most pronounced when drug administration occurred at times surrounding antigen sensitization. To further evaluate the direct effect of delta 9-THC on T-cell function, T-cell proliferative responses to stimulation by anti-CD3 monoclonal antibodies were measured. delta 9-THC was found to produce a marked and dose related inhibition of anti-CD3 mAb-induced T-cell proliferation which was cell density dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Delta 9-tetrahydrocannabinol selectively inhibits T-cell dependent humoral immune responses through direct inhibition of accessory T-cell function. 828 37

delta 9-Tetrahydrocannabinol (delta 9-THC) a prototypic compound belonging to the family of agents known as cannabinoids, produces a wide variety of biological effects, including inhibition of immune function. The putative mechanism for cannabinoid biological action involves binding to cannabinoid receptor types 1 and 2 (CB1 and CB2) to negatively regulate adenylate cyclase and inhibit intracellular signaling via the cAMP cascade. In the current study, we show that delta 9-THC produces a marked inhibition of inducible nitric oxide synthase (iNOS) transcription and nitric oxide production by the macrophage line RAW 264.7 in response to lipopolysaccharide (LPS). Analysis of RAW 264.7 cell RNA demonstrated transcripts for CB2 but not CB1. Treatment of RAW 264.7 with delta 9-THC inhibited forskolin-stimulated cAMP production in a dose-related manner, verifying the expression of functional cannabinoid receptors by this cell line. iNOS transcription, which is regulated in part by the nuclear factor-kappa B/Rel (NF-kappa B/Rel) family of transcription factors, has been shown to be under the control of the cAMP signaling cascade. We demonstrate that delta 9-THC inhibits the activation and binding of NF-kappa B/Rel proteins to their cognate DNA site, kappa B, in response to LPS stimulation. LPS treatment of RAW 264.7 cells also induced the activation of the cAMP cascade, as indicated by an increase in binding of nuclear factors to the cAMP response element. Activation of CRE binding proteins was inhibited by delta 9-THC. Forskolin treatment of RAW 264.7 cells induced both kappa B and cAMP response element binding activity and was likewise inhibited by delta 9-THC. Collectively, this series of experiments indicates that NF-kappa B/Rel is positively regulated by the cAMP cascade to help initiate iNOS gene expression in response to LPS stimulation of macrophages. This activation of iNOS is attenuated by delta 9-THC through the inhibition of cAMP signaling.
 ...
PMID:Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. 870 Jan 41

delta 9-Tetrahydrocannabinol (THC) inhibited nitric oxide (NO) production by mouse peritoneal macrophages activated by bacterial endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN)-gamma). Inhibition of NO production was noted at THC concentrations as low as 0.5 microgram/mL, and was nearly total at 7 micrograms/mL. Inhibition was greatest if THC was added 1-4 hr before induction of nitric oxide synthase (NOS) by LPS and IFN-gamma, and declined with time after addition of the inducing agents. This suggested that an early step such as NOS gene transcription or NOS synthesis, rather than NOS activity, was affected by THC. Steady-state levels of mRNA for NOS were not affected by THC. In contrast, protein synthesis was inhibited as indicated by immunoblotting. NOS activity was also decreased in the cytosol of cells pretreated with THC. Addition of excess cofactors did not restore activity. Inhibition of NO production was greater at low levels of IFN-gamma, indicating the ability of the cytokine to overcome inhibition. The effectiveness of various THC analogues, in decreasing order of potency, was delta 8-THC > delta 9-THC > cannabidiol > or = 11-OH-THC > cannabinol. The presumably inactive stereoisomer, (+)delta 9-THC, and the endogenous ligand for cannabinoid receptors, anandamide, were weakly inhibitory. Inhibition may be mediated by a process that depends partly on stereoselective receptors and partly on a nonselective process. LPS, IFN-gamma, hormone receptor agonists, and forskolin increased macrophage cyclic AMP levels. THC inhibited this increase, indicating functional cannabinoid receptors. Addition of 8-bromocyclic AMP increased NO 2-fold, and partially restored NO production that had been inhibited by THC. This occurred only under conditions of limited NOS induction, suggesting that the effect of THC on cyclic AMP was responsible for only a small portion of the inhibition of NO.
 ...
PMID:Tetrahydrocannabinol inhibition of macrophage nitric oxide production. 876 72