Cannabinoid Treatment Suppresses the T-Helper Cell-Polarizing Function of Mouse Dendritic Cells Stimulated withLegionella pneumophilaInfection

Abstract

Marijuana cannabinoids, such as ␦-9-tetrahydrocannabinoid (THC), suppress type 1 T-helper 1 (Th1) immunity in a variety of models, including infection with the intracellular pathogen Legionella pneumophila (Lp). To examine the cellular mechanism of this effect, bone marrow-derived dendritic cells (DCs) were purified from BALB/c mice and studied following infection and drug treatment. DCs infected in vitro with Lp were able to protect mice when injected prior to a lethal Lp infection; however, the immunization potential of the Lp-loaded cells along with Th1 cytokine production was attenuated by THC treatment at the time of in vitro infection. In addition, THC-treated and Lp-loaded DCs were poorly stimulated in culture-primed splenic CD4ϩ T cells to produce interferon-␥; however, this stimulating deficiency was reversed by adding recombinant interleukin (IL)-12p40 protein to the cultures. Moreover, THC treatment inhibited the expression of DC maturation markers, such as major histocompatibility complex class II and costimulatory molecules CD86 and CD40 as determined by flow cytometry and suppressed the Notch ligand, Delta4, as determined by reverse transcription-polymerase chain reaction. However, THC treatment did not affect other DC functions, such as intracellular killing of Lp, determined by colony-forming unit counts of bacteria, and Lp-induced apoptosis, determined by annexin V staining. In conclusion, the data suggest that THC inhibits Th1 activation by targeting essential DC functions, such as IL-12p40 secretion, maturation, and expression of costimulatory and polarizing molecules.

Modulation of Airway Responses to Influenza A/PR/8/34 by Δ9-Tetrahydrocannabinol in C57BL/6 Mice

“…These findings were supported by histopathology and are consistent with similar studies that demonstrated increased susceptibility to the respiratory pathogen, Legionella pneumophila, after ⌬ 9 -THC administration (Klein et al, 2000). As in the present study with PR8, Klein and coworkers similarly showed that ⌬ 9 -THC affected T cell and macrophage function as suggested by altered regulation of T cell-derived cytokines and a suppression of T cell activation to Legionella by attenuation of the expression of costimulatory and polarizing molecules on the antigen-presenting dendritic cells (Klein et al, 2000;Lu et al, 2006). Further studies will need to be conducted to determine the effects of ⌬ 9 -THC on the later stages of the immune response to PR8, as well as to ascertain the role of cannabinoid receptors, CB1 and CB2, on the ⌬ 9 -THC-mediated effects observed.…”

Suppression of Dendritic Cell Activation by Anthrax Lethal Toxin and Edema Toxin Depends on Multiple Factors Including Cell Source, Stimulus Used, and Function Tested

“…To date, the effect of anthrax toxins on DC maturation to only two microbial antigens, LPS and anthrax spores, has been reported. To more fully understand toxin effects, we wanted to study cells treated with a third type of stimulus, Legionella, a bacterial agent known to infect and alter DC maturation (Lu et al, 2006a(Lu et al, , 2006bRogers et al, 2007). Our findings show that LT and ET can either enhance Culture supernatants were harvested and analyzed by ELISA.…”

“…Our lab has previously shown that infection of DCs with Legionella induces a spectrum of cellular changes consistent with Th1 immune polarization (Lu et al, 2006a(Lu et al, , 2006bNewton et al, 2007). Lp infection stimulated the production of polarizing cytokines such as IL-12, IL-6, and TNF-a along with increased MHC class II expression (Lu et al, 2006a(Lu et al, , 2006bNewton et al, 2007). In addition, unlike LPS stimulation, Lp stimulates DCs through TLR 2 and TLR 9 rather than TLR 4 .…”

“…This disease is prevalent among immunecompromised individuals, including young children, aged persons, transplant patients, patients receiving corticosteroids, and patients suffering from AIDS (Kikuchi et al, 2005). Our lab has previously shown that infection of DCs with Legionella induces a spectrum of cellular changes consistent with Th1 immune polarization (Lu et al, 2006a(Lu et al, , 2006bNewton et al, 2007). Lp infection stimulated the production of polarizing cytokines such as IL-12, IL-6, and TNF-a along with increased MHC class II expression (Lu et al, 2006a(Lu et al, , 2006bNewton et al, 2007).…”

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

“…O'Sullivan et al 14 demonstrated that ⌬9-tetrahydrocannabinol causes vasorelaxation through activation of PPAR␥. Both CB2 and PPAR␥ agonists reduce MPO activity 29,69 and increase a T H 2 cytokine profile 68,70 in experimental colitis in mice. In addition, the activation of CB2 and/or PPAR␥ significantly reduces CXCL1/KC and MIP-2 tissue levels 71,72 and inhibits NF B, IKK␣/␤, and CREB activation.…”