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9-Tetrahydrocannabinol Treatment Suppresses Immunity and Early IFN-
, IL-12, and IL-12 Receptor ß2 Responses to Legionella pneumophila Infection1
Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, FL 33612
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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9-tetrahydrocannabinol
(THC), suppresses immunity to Legionella pneumophila and
development of Th1 activity and cell-mediated immunity. In the current
study, THC effects on cytokines regulating the development of Th1 cells
were examined. BALB/c mice showed significant increases in serum IL-12
and IFN-
within hours of infection; however, the levels of these
Th1-promoting cytokines as well as resistance to a challenge infection
were suppressed by THC (8 mg/kg) injected 18 h before priming. The
Th2-promoting cytokine, IL-4, was increased within hours of a
Legionella infection and was further increased by THC
treatment. These results suggested that THC injection suppressed the
cytokine environment promoting Th1 immunity. In additional experiments,
THC pretreatment and infection of IL-4 knockout mice showed that serum
IL-12 and IFN- were suppressed equally in both knockout and normal
mice. This suggested that the drug-induced increase in IL-4 was not
responsible for the decreases in serum IL-12 and IFN-. However, THC
treatment was shown to suppress the expression of IL-12 receptor ß2
mRNA, indicating that, in addition to suppression of IL-12, THC
injection suppressed the expression of IL-12 receptors. Finally, the
role of cannabinoid receptors in Th1-promoting cytokine suppression was
examined, and results with receptor antagonists showed that both
cannabinoid receptors 1 and 2 were involved. It is suggested that
suppression of Th1 immunity to Legionella is not due to
an increase in IL-4 production but to a decrease in IFN- and IL-12.
Furthermore, both types of cannabinoid receptors are
involved. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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9-tetrahydrocannabinol
(THC)3 (1, 2). This drug and various analogues produce effects by binding
to cannabinoid receptors in the brain and periphery, and recent
evidence suggests that cannabinoid receptor 1 (CB1) is expressed in the
former while cannabinoid receptor 2 (CB2) is expressed in the latter
(3). Endogenous ligands for cannabinoid receptors derived
from arachidonic acid have also been described, thus supporting the
existence of a complete endogenous cannabinoid system of receptors and
ligands (4). The purpose and function of this system is
currently under investigation.
Besides psychoactivity, THC and other cannabimimetic agents have been
shown to modulate immune function in animals and humans
(5). However, the impact of these effects on human health
and disease is unclear, and the involvement of cannabinoid receptors is
also unclear. The possible adverse effects of marijuana and
cannabinoids on immunity to infection is of particular concern, and we
have begun testing the possibility that THC might compromise host
resistance to infection with opportunistic bacterial agents such as
Legionella pneumophila. We have developed a mouse model of
Legionella infection that displays many of the cellular and
cytokine features involved in immunity to many other intracellular
bacteria including the activation of Th1 cells and cell-mediated
immunity (CMI) (6, 7, 8). For example, splenocytes from
sublethally infected mice become sensitized and proliferate to a
greater extent and produce more IFN- when stimulated with
Legionella Ags. Furthermore, reinfection of the mice induces
an increase in these responses and an increase in splenic and PBL T
cells (6). Th1 activity is also increased following
Legionella infection (8). Within 4–5 days,
IgG2a Ab and splenocyte IFN- production are on the rise, and these
responses precede the development of immune memory to
Legionella infection. Previously, we reported that the
injection of THC in this model suppressed the memory response and the
development of Th1 activity and increased the Th2-associated response,
IgG1 Abs to Legionella (8). Recent evidence has
now established that the relative differentiation of Th1 and Th2 cells
depends in part on the action of either IL-12 or IL-4 (9),
with IL-12 causing the generation of Th1 cells while IL-4 inducing Th2
cells. In the current report, we show that suppression by THC of
Th1-promoting cytokines is not due to an increase in IL-4 but more
likely due to suppression in the production of IFN-, IL-12, and
IL-12 receptor ß2 (IL-12Rß2). In addition, we show that CB1 and CB2
antagonists attenuate the drug effects on cytokine production,
suggesting that both receptor subtypes are involved in the modulation
of immunity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serogroup 1, L. pneumophila, isolated from a case of Legionnaires’ disease at Tampa General Hospital was grown on buffered charcoal yeast extract plates (Difco, Detroit, MI) for 48 h from a passage no. 3 stock maintained at -80°C. This strain is highly virulent for guinea pigs and readily grows in macrophage cultures (10). SR141716A, a CB1 antagonist, was a generous gift from M. Rinaldi-Carmona (Sanofi Recherche, Montpellier, France), and SR144528, a CB2 antagonist, as well as THC were obtained from the Research Technology Branch of the National Institute on Drug Abuse. The antagonists and THC were initially diluted in DMSO to either 50 mg/ml (THC) or 25 mg/ml (antagonist). They were then diluted 1:25 in normal mouse serum to either 2 mg/ml (THC) or 1 mg/ml (antagonist). These were then injected i.v. into mice to yield doses of either 8 or 4 mg/kg. For vehicle control injections, mice received i.v. 0.1 ml of DMSO diluted 1:25 in normal mouse serum.
Animal injections and tissue sampling
Female BALB/cByJ mice and
BALB/c-IL-4-tm2Nnt knockout mice
(11) (The Jackson Laboratory, Bar Harbor, ME), 7–8 wk of
age, were housed and cared for in the University of South Florida
animal facility, which is fully accredited by the American Association
for Accreditation of Laboratory Animal Care. Normal mice were primed
via the tail vein with 
7 x 106Legionella suspended in saline, while knockout mice, which were
more susceptible to the priming infection with Legionella,
were infected with fewer bacteria (3 x
106). For challenge infection, mice were injected
with 5 x 107 Legionella. For
drug treatment, THC (8 mg/kg) or the equivalent amount of drug vehicle
(DMSO) diluted in serum was injected i.v. 18 h before infection,
and the antagonists (4 mg/kg) diluted in serum, when used, were
injected i.v. 30 min before THC. For mortality tests, the mice were
observed continuously following Legionella infection, and
those that became moribund were euthanized by CO2
asphyxiation and added to the mortality total. Blood, collected by
cardiac puncture, and spleens were obtained at the times indicated
after infection and processed for cytokine analysis. Single-cell
suspensions of splenocytes were cultured in RPMI 1640 medium (Sigma,
St. Louis, MO) supplemented with 10% heat-inactivated FCS (HyClone,
Logan, UT), 2-ME (5 µM), and antibiotics for 3 h for the IL-4
determinations.
ELISA
IL-4, IL-12, and IFN- assays were determined using sandwich
ELISAs with Ab pairs from PharMingen (San Diego, CA). Medium-bind,
96-well enzyme immunoassay plates (Costar, Cambridge, MA) were coated
with 50 µl of capture Ab in PBS (anti-IFN-, 4 µg/ml;
anti-IL-4, 2 µg/ml) or in 0.1 M NaHCO3, pH
8.2 (anti-IL-12 p40/p70, 10 µg/ml), overnight at 4°C. The
plates were blocked for 30 min with 150 µl of 0.5% BSA/0.05% Tween
20/PBS (IFN-, IL-4) or for 2 h with 3% BSA in PBS (IL-12). The
culture supernatants, sera, or serial dilutions of cytokine standards
were added for 1–2 h. Biotinylated detection Abs (IFN- and IL-12, 2
µg/ml; IL-4, 1 µg/ml) were added in 50-µl volumes for 1 h,
followed by streptavidin-HRP (1:1000 in 50 µl) for 30 min. After the
substrates were added, plates were developed for 5–45 min. The HRP
reaction was stopped with 1 N sulfuric acid. The reactions were read at
450 nm (HRP) on an Emax microplate reader (Molecular Devices, Menlo
Park, CA). Sample cytokine concentrations were generated from standard
curves.
RT-PCR
Total RNA was extracted from mouse spleens by standard techniques using TriReagent (Sigma; 1 ml per 2 x 107 cells) and quantitated using RiboGreen RNA Quantitation Kit (Molecular Probes, Eugene, OR). The cDNAs were synthesized at 42°C for 45 min from 1 µg of total RNA by priming with 0.5 µg oligo(dT)15 primer, 20 nmol each deoxynucleoside triphosphate, 0.5 U RNase inhibitor, and 15 U avian myeloblastosis virus reverse transcriptase (Promega, Madison, WI) in a final volume of 25 µl. The reverse transcriptase product, equivalent to 0.1 µg starting RNA, was used for PCR with mouse primers for IL-12Rß2 (12) (5'-GAGTACATAGTGGAATGGAGAG-3' and 5'-TCACAGCTGTCATCCATAGGAC-3') and ß-actin (13) (5'-ATGGATGACGATATCGCT-3' and 5'-ATGAGGTAGTCTGTCAGGT-3'). The PCR was performed in a Minicycler (MJ Research, Watertown, MS) for either 27 cycles and 63°C annealing (IL-12R) or 23 cycles and 63°C annealing (ß-actin). PCR products were analyzed on ethidium bromide-stained, 2% agarose gels and quantitated and normalized to ß-actin using densitometry readings (Bio-Rad, Hercules, CA). The data are presented as the ratio of IL-12R to ß-actin densities for pools of mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice are relatively resistant to a challenge infection with
Legionella. For example, they will survive bacterial doses
of up to 107 bacteria administered i.v. However,
they will succumb to higher doses unless they have been primed or
immunized by a prior Ag exposure (8). In the current
studies, individual mice were either nonprimed or primed with an
injection of 7 x 106 viable
Legionella following DMSO treatment. The mice were rested
for 3 wk and challenged with a lethal dose of 5 x
107 bacteria. Fig. 1
shows that this dose of bacteria was
uniformly lethal in the nonprimed group, with 50 of 50 mice dying.
However, mice primed with a Legionella infection were
totally resistant to the challenge infection, with 0 deaths occurring
among 35 animals. To test the effect of THC on this immunization,
animals were injected i.v. with THC (8 mg/kg) 18 h before the
immunizing infection. As seen in Fig. 1, these animals were very
susceptible to the challenge infection with approximately two-thirds
(23 of 35 mice) succumbing to the infection. Because CMI must develop
in the mice between the priming and challenge infections for the
animals to survive (7, 8), these results suggested that
THC treatment suppressed this response.
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Immunity to Legionella infection, as with many other
facultative intracellular microbes, depends on the preferential
development or polarization of Th1 cells over Th2 cells (14, 15). Mice infected with Legionella have been shown to
preferentially mobilize Th1 cytokines in their immune tissues
(8), and humans recovering from Legionella
pneumonia show a predominance in serum of Th1-promoting cytokines such
as IL-12 and IFN- over Th2-promoting cytokines such as IL-4 and
IL-10 (16). We wanted to see if THC injection altered the
cytokine environment promoting Th1 development. Mice were injected with
either THC or DMSO, infected with Legionella as in Fig. 1
above, and bled at various times after infection. Serum was analyzed
for IL-12 and IFN- by ELISA, and it was observed that in control
mice both cytokines peaked in serum between 3 and 24 h;
furthermore, it was observed that drug treatment decreased this
cytokine mobilization (Fig. 2,
A and B). IL-4 was not detected in serum at this
time but could be demonstrated in splenocytes removed from the mice and
cultured in vitro. Interestingly, instead of THC treatment decreasing
IL-4 production, it increased the production (Fig. 2C).
These results suggested that THC treatment caused an immune deviation
from the expected Th1-promoting environment.
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in IL-4 knockout mice
The decrease observed in IL-12 and IFN- production could stem
from a variety of causes including an increase in IL-4 production that
has been shown to suppress the production of IFN- (17, 18). Indeed, THC-treated animals display heightened IL-4
activity in the spleen (Fig. 2C). Disruption of the IL-4
gene has been used to study the role of IL-4 in the differentiation of
Th cells (19), and we employed this model to study the
role of IL-4 in the THC-induced decrease in IFN- and IL-12
production. In our hands, the knockout mice differed from wild-type
animals only in their sensitivity to the priming infection with
Legionella. This appears to be due to the inability to
regulate acute-phase cytokine mobilization (C. Newton, manuscript
in preparation). Otherwise, the knockouts developed Th1 immunity and
presented the same disease symptoms when challenged with
Legionella or treated with THC. IL-4 knockout mice were
infected with Legionella and treated with THC as above. At 5
and 8 h following infection, bloods were removed and IFN- and
IL-12 were measured in the sera by ELISA. Fig. 3 shows that both cytokines were
suppressed by THC treatment at 8 h after infection in both
knockout mice as well as in mice containing the intact IL-4 gene.
Similar results were obtained at 5 h (data not shown). Because the
knockout mice produced no IL-4 (data not shown), it was concluded that
the suppression of Th1-promoting cytokines was not due to heightened
production of IL-4.
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The development of Th1 cells is dependent on the expression and
function of the IL-12 system including both the cytokine produced by
macrophages and NK cells (20) and IL-12 receptors composed
of two subunits, ß1 and ß2 (21). Both of these
subunits appear to be important in the functioning of the IL-12
receptor (21, 22), and therefore we tested to see if THC
altered the production of IL-12Rß2. Groups of mice were either
noninjected or injected with either DMSO or THC followed 18 h
later by Legionella infection. At various times after
infection, individual spleens were removed and processed for RT-PCR to
measure mRNA for IL-12Rß2 and the control gene, ß-actin. Fig. 4 shows pooled data from 81 individual
mice treated in the ways indicated, and data are presented as the
means ± SEM of the densitometry ratios for each group of animals.
These normalized results showed that Legionella infection
rapidly increased the expression of IL-12Rß2 message in the spleen up
through 5 h after infection. However, prior THC treatment
significantly suppressed the message expression at all time points
following infection. These results suggested that THC treatment
suppressed the expression of the IL-12Rß2 subunit gene and therefore
possibly suppressed the receptor expression and function in the spleen
of infected mice.
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Controversy exists concerning the role of cannabinoid receptors in
THC-induced immunomodulation (5). Therefore, it was
important to examine the involvement of CB1 and CB2 in the observed
drug-induced suppression. Specific antagonists have been described that
block the activity of cannabinoid receptors. For example, SR141716A
inhibits CB1 (23) and SR144528 inhibits CB2
(24). Therefore, we injected mice with either antagonist
compound (4 mg/kg) 30 min before THC treatment. As expected, the CB1
antagonist suppressed the catalepsy response (25) of the
mice, while the CB2 antagonist had no effect in this regard (data not
shown). Fig. 5, A and
B show that both antagonists reversed at 8 h the
suppressive effect of THC on the serum levels of IFN- and IL-12,
respectively, suggesting that both receptors were involved. Similar
results were observed at 5 h (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Mice that were
sublethally infected were shown to be completely resistant to a lethal
challenge infection 3 wk later (Fig. 1). Using this animal model, we
asked the question what effect THC administration would have on CMI
development if given around the time of immune priming and activation.
Our results definitively show that THC injection into mice shortly
before the priming infection inhibits the development of protective
immunity, thus leaving the animal susceptible to a subsequent challenge
infection with a lethal dose of bacteria (Fig. 1). These results
support our previous findings (8) and firmly establish
that a relatively low dose of THC (8 mg/kg) can suppress the
development of a protective immune response.
Immunity to Legionella infection, as with many other
facultative intracellular bacteria, depends on the preferential
development or polarization of Th1 cells over Th2 cells (14, 15). Our previous work (8) suggested that THC
treatment suppressed Th1 activity, and therefore we wanted to examine
this model further to determine whether the drug treatment suppressed
the formation of cytokines that promote Th1 activity. In vivo cytokine
levels can be analyzed in several ways in animals and humans undergoing
immune stimulation. For example, tissues such as spleen and liver
(28) can be removed and tested in culture; alternatively,
serum can be removed and tested by ELISA (16, 29). Fig. 2
shows that mice infected with Legionella displayed readily
detectable levels of IL-12 and IFN- in serum, reaching a peak
between 8 and 24 h after infection. The cellular sources of these
Th1-biasing cytokines were probably macrophages and NK cells as shown
in other infection models (15, 20); in addition, T cells
might also contribute as a source of these cytokines (our unpublished
observation). Our IFN- results differ from a previous report that
showed serum IFN- reached a peak at 24 h after
Legionella infection (29). However, this
difference is probably related to either variations in mouse strain or
route of infection. We used the less susceptible strain, BALB/c, and
our infections were done i.v., while the previous study used the more
susceptible A/J strain of mice and inoculated the mice intratracheally
(29). We also tested for the Th2-biasing cytokine, IL-4,
but this was not detectable in the serum samples; however, it was
detected in supernatants of cultured splenocytes removed within hours
following infection (Fig. 2C) and was observed to increase
through 5 h. This early increase in IL-4 has been observed by
others (30), and although IL-4 generally biases toward the
development of Th2 cells it can have a positive effect on Th1
development under the right conditions (31, 32). Regarding
the effect of THC injection, it was observed to significantly decrease
the serum level of IL-12 and IFN- but increase the supernatant level
of IL-4 (Fig. 2). These results coupled with our previous findings
(6, 8) show that treatment suppresses the development of
Th1 immunity leading to increased susceptibility to
Legionella infection.
Th1 cells produce cytokines such as IFN- that promote the resistance
to and elimination of intracellular bacteria such Legionella
(15). The development of Th1 cells from Ag-activated
precursor cells requires the presence of IL-12 and IFN- as well as
the presence of specialized dendritic cells (33). However,
the presence of IL-4 can have an inhibitory effect on Th1 cell
development (17, 18, 34), and because drug treatment
increased the splenocyte production of IL-4 (see Fig. 2) we wanted to
determine whether THC suppression of IL-12 and IFN- occurred in IL-4
knockout mice. The results showed (Fig. 3) that knockout mice were
similar to intact mice in that the drug treatment reduced Th1-biasing
cytokines, suggesting that THC was suppressing immunity by a mechanism
other than increasing IL-4 production.
Th1 cell development is also attenuated by a down-regulation of IL-12R
subunits (21, 22), and so we tested if THC treatment was
in some way inhibiting the expression of these receptors. We found that
splenocytes removed from mice after drug treatment and infection showed
less IL-12Rß2 mRNA by RT-PCR than did nontreated animals (Fig. 4),
suggesting that the expression of this receptor subunit is inhibited in
some way by the drug. Although, in this study, we did not define the
cell type or types with depressed IL-12R mRNA, it is possible that both
T cells and splenic adherent cells are affected because in preliminary
purification studies (not shown) both cell types were observed to
express IL-12R mRNA within hours of infection. The IL-12R complex is
composed of two subunits, ß1 and ß2, belonging to the ß-type
cytokine receptor group (35). Both receptor proteins must
be expressed for high-affinity binding of IL-12, and both are of
importance in cell signaling following binding of IL-12. A decrease in
expression of the ß2 subunit mRNA as observed in our study has been
correlated with a decrease in responsiveness to IL-12 and Th1
activation (22), and therefore it is possible that this
effect of the drug is at least partially responsible for the decrease
in CMI. However, demonstration of a decrease in subunit protein on
splenocyte subsets is needed and is currently under investigation. As
to how the drug is suppressing the expression of ß2 mRNA, the
induction of inhibitory cytokines such as IL-4, TGF-ß, and IL-10
(22, 35) are a possibility, and we have observed
that THC increases IL-4 (Fig. 2) as well as TGF-ß and IL-10 in mice
(our unpublished observations).
THC can exert its effects by both cannabinoid receptor- and
nonreceptor-mediated mechanisms (36). The nonreceptor
mechanism might involve insertion of the THC into the cell membrane
lipid bilayer altering the function of membrane proteins
(37). Receptor mechanisms would be mediated through the
action of either CB1 or CB2 expressed in both the brain and peripheral
tissues including the immune system (3). Elucidating the
role of receptor involvement has been facilitated by the discovery of
CB1 and CB2 antagonists (23, 24), and we employed these
drugs to determine whether either receptor was involved in the THC
effect. The results showed that both antagonists attenuated the drug
effects on IL-12 and IFN-, supporting the conclusion that both
receptors are involved (Fig. 5). Because there is evidence that CB1 and
CB2 are expressed on cells of the immune system (5), it is
possible that THC is acting directly on these cells (see below).
However, CB1 receptors are also expressed in various regions of the
brain such as the hippocampus and amygdala (38). These
regions can regulate the hypothalamus (39) and thus
regulate the hypothalamo-pituitary-adrenal axis, a known modulator of
immune function (40). Therefore, it is possible that
THC-induced increases in pituitary and adrenal hormones are modulating
in our system. Indeed, injection of THC into rats causes a rapid
increase in serum adrenocorticotropic hormone and corticosterone as
well as a depletion of hypothalamic corticotropin-releasing factor,
demonstrating this hypothalamo-pituitary-adrenal effect
(41), and this steroid mobilization was implicated in
immune modulation (42). Corticosteroids have also been
reported to have effects on Th cells, favoring the development of Th2
responses over Th1 (43, 44, 45), which is consistent with our
findings. Also consistent is a recent report (46) showing
that dexamethasone treatment of immune cells suppressed the expression
of IL-12R subunits similar to what we have observed. We are currently
testing for an increase in corticosterone in our animals and will also
look for an inhibitory function of RU486 in attenuating the THC effect
on cytokine production.
THC injection might also be affecting immune cells directly through interaction with CB1 and CB2. These receptors are G protein-coupled receptors that are negatively coupled to adenylyl cyclase (47), and this coupling occurs in cells of the immune system (48). However, more recently, receptor ligation of CB1 in the presence of the Gi inhibitor, pertussis toxin, uncovered a stimulatory effect on adenylyl cyclase and an increase in cellular cAMP (49, 50). Therefore, it is possible that stimulation of immune cell CB1 or CB2 might either increase or decrease cAMP and various associated functions. For example, others have shown that increasing cAMP decreases IL-12 and IL12R proteins (46, 51, 52) but increases IL-10 (53). This is similar to what we have observed. Increasing cAMP can also interrupt the JAK-STAT signaling pathway important in cytokine cell signaling (54). In contrast, the production of IL-4 by lymphocytes can be suppressed by cAMP (55), which is the reverse of what we observed following THC injection.
Finally, another mechanism that might account for the effects observed in our studies involves the mobilization of arachidonic acid and PGE following THC injection. This effect was noted a number of years ago (56) and has more recently been shown to occur by cannabinoid receptor-mediated mechanisms (57) in cells of the immune system (58). PGE has been shown to either increase or decrease Th cytokines depending upon the protocol employed (46, 55, 59), and therefore mobilization by THC injection might account for some of the effects we have observed. We are currently examining the effect of indomethacin injection on the THC-induced modulation of Th cytokine.
In summary, the effect of THC on cytokines promoting the development of Th1 cells involves cannabinoid receptors and probably a variety of other physiologic and molecular mechanisms. This complexity of mechanisms for THC is significantly compounded when trying to understand the effects and mechanisms of action of marijuana smoke in various immune systems. Clearly, more studies are needed to understand these drug effects as well as understand the role of cannabinoid receptors in host defenses.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas W. Klein, Department of Medical Microbiology And Immunology, MDC Box 10, University of South Florida, 12901 Bruce Downs Boulevard, Tampa, FL 33612.
3 Abbreviations used in this paper: THC, 9-tetrahydrocannabinol; CMI, cell-mediated immunity; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; IL-12Rß2; IL-12 receptor ß2.
Received for publication September 20, 1999. Accepted for publication March 29, 2000.
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B. L. F. Kaplan, Y. Ouyang, C. E. Rockwell, G. K. Rao, and N. E. Kaminski 2-Arachidonoyl-glycerol suppresses interferon-{gamma} production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2 J. Leukoc. Biol., June 1, 2005; 77(6): 966 - 974. [Abstract] [Full Text] [PDF]
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 R. J. McKallip, M. Nagarkatti, and P. S. Nagarkatti {Delta}-9-Tetrahydrocannabinol Enhances Breast Cancer Growth and Metastasis by Suppression of the Antitumor Immune Response J. Immunol., March 15, 2005; 174(6): 3281 - 3289. [Abstract] [Full Text] [PDF]
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C. A. Newton, T. Lu, S. J. Nazian, I. Perkins, H. Friedman, and T. W. Klein The THC-induced suppression of Th1 polarization in response to Legionella pneumophila infection is not mediated by increases in corticosterone and PGE2 J. Leukoc. Biol., October 1, 2004; 76(4): 854 - 861. [Abstract] [Full Text] [PDF]
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Y. Do, R. J. McKallip, M. Nagarkatti, and P. S. Nagarkatti Activation through Cannabinoid Receptors 1 and 2 on Dendritic Cells Triggers NF-{kappa}B-Dependent Apoptosis: Novel Role for Endogenous and Exogenous Cannabinoids in Immunoregulation J. Immunol., August 15, 2004; 173(4): 2373 - 2382. [Abstract] [Full Text] [PDF]
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T. W. Klein, C. Newton, K. Larsen, L. Lu, I. Perkins, L. Nong, and H. Friedman The cannabinoid system and immune modulation J. Leukoc. Biol., October 1, 2003; 74(4): 486 - 496. [Abstract] [Full Text] [PDF]
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 J. Roig and J. Rello Legionnaires' disease: a rational approach to therapy J. Antimicrob. Chemother., May 1, 2003; 51(5): 1119 - 1129. [Abstract] [Full Text] [PDF]
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 H. Friedman, C. Newton, and T. W. Klein Microbial Infections, Immunomodulation, and Drugs of Abuse Clin. Microbiol. Rev., April 1, 2003; 16(2): 209 - 219. [Abstract] [Full Text] [PDF]
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R. J. McKallip, C. Lombard, B. R. Martin, M. Nagarkatti, and P. S. Nagarkatti Delta 9-Tetrahydrocannabinol-Induced Apoptosis in the Thymus and Spleen as a Mechanism of Immunosuppression in Vitro and in Vivo J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 451 - 465. [Abstract] [Full Text] [PDF]
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A. C. Howlett, F. Barth, T. I. Bonner, G. Cabral, P. Casellas, W. A. Devane, C. C. Felder, M. Herkenham, K. Mackie, B. R. Martin, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors Pharmacol. Rev., June 1, 2002; 54(2): 161 - 202. [Abstract] [Full Text] [PDF]
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S. Salins, C. Newton, R. Widen, T. W. Klein, and H. Friedman Differential Induction of Gamma Interferon in Legionella pneumophila- Infected Macrophages from BALB/c and A/J Mice Infect. Immun., June 1, 2001; 69(6): 3605 - 3610. [Abstract] [Full Text] [PDF]
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 T. W. Klein, B. Lane, C. A. Newton, and H. Friedman The Cannabinoid System and Cytokine Network Experimental Biology and Medicine, October 1, 2000; 225(1): 1 - 8. [Abstract] [Full Text]
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A. Elhofy, I. Marriott, and K. L. Bost Salmonella Infection Does Not Increase Expression and Activity of the High Affinity IL-12 Receptor J. Immunol., September 15, 2000; 165(6): 3324 - 3332. [Abstract] [Full Text] [PDF]
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