Cocaine modulates cytokine and enhances tumor growth through sigma receptors
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Transcript of Cocaine modulates cytokine and enhances tumor growth through sigma receptors
www.elsevier.com/locate/jneuroim
Journal of Neuroimmunology 147 (2004) 95–98
Cocaine modulates cytokine and enhances tumor growth
through sigma receptors
Brian Gardnera,b,*, Li X. Zhua, Michael D. Rotha,c, Donald P. Tashkina,c,Steven M. Dubinetta,b,c, Sherven Sharmaa,b,*
aDivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at the University of California-Los Angeles,
Los Angeles, CA 90095, USAbDivision of Pulmonary and Critical Care Medicine, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
cUCLA Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA
Abstract
Sigma receptors are intracellular receptors that interact with a variety of psychotropic ligands, including cocaine. Administration of
cocaine to mice promoted the in vivo growth of a syngeneic lung cancer cell line and identical effects were observed with PRE 084, a
selective sigma1 receptor agonist. Increased tumor growth was accompanied by an increase in IL-10 and a decrease in IFN-g production in
splenocytes and at the tumor site. The tumor-promoting effects produced by both cocaine and PRE 084 were abrogated by administration of
specific antibodies to IL-10, or by administration of a sigma1 receptor antagonist. We conclude that sigma1 receptor ligands, including
cocaine, augment tumor growth via a cytokine-dependent, receptor-mediated mechanism that involves regulation of T helper 1/T helper 2
cytokine balance.
D 2003 Elsevier B.V. All rights reserved.
Keywords: Cocaine; Sigma receptor; Tumor; Cytokine; Interleukin-10; Immunity
1. Introduction
Sigma receptors are a unique family of intracellular
receptors found in neuronal tissues, cells of the immune
system, (Liu et al., 1995; Ganapathy et al., 1999) and also in
human and murine tumors (John et al., 1995; Vilner et al.,
1995). These receptors interact with a variety of compounds
including cocaine, dextromethorphan and benzomorphans
(Walker et al., 1990). At least two subtypes of sigma
receptors, classified as sigma1 and sigma2, are distinguish-
able by their physiological function and pharmacological
response.
Sigma ligands have potent regulatory effects on cyto-
kines including the induction of IL-10 (Bourrie et al.,
0165-5728/$ - see front matter D 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jneuroim.2003.10.020
* Corresponding authors. UCLA Lung Cancer Research Program,
David Geffen School of Medicine at UCLA, 37-131 Center for Health
Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690, USA.
Tel.: +1-310-478-3711x41863; fax: +1-310-268-4164.
E-mail addresses: [email protected] (B. Gardner),
[email protected] (S. Sharma).
1995) and the suppression of IFN-g and GM-CSF (Carayon
et al., 1995). In murine studies, treatment with sigma
ligands prevented both graft-versus-host disease and
delayed-type hypersensitivity granuloma formation (Car-
ayon et al., 1995). These studies indicate that sigma
receptor signaling can regulate immune responses. Co-
caine has been reported to be a sigma1 receptor ligand
and to modulate immune function in vivo and in vitro
(Pellegrino and Bayer, 1998; Xu et al., 1999). Cocaine
down-regulates the production of IFN-g by human pe-
ripheral blood leukocytes and increases the production of
TGF-h by endothelial cells and macrophages (Mattana et
al., 1994; Mao et al., 1996; Mao et al., 1997). Alveolar
macrophages isolated from crack cocaine smokers exhibit
depressed antimicrobial activity compared to nonsmokers
(Baldwin et al., 1997). Their capacity to kill Staphylo-
coccus aureus was restored by the addition of exogenous
GM-CSF or IFN-g, suggesting that exposure to crack
cocaine inhibited the production of these cytokines in
vivo (Shay et al., 2003). Cocaine also enhances HIV-1
replication in stimulated peripheral blood mononuclear
cells in a TGF-h dependent manner (Peterson et al.,
Table 1
Enhanced in vivo tumor growth produced by administration of cocaine or
PRE 084 was abrogated by BD1047, a selective sigma1 receptor antagonist
Groupa Pretreatment
with BD1047bTumor size at
day 21 (cm3)cP
valued
Control � 817F 60
Cocaine-treated � 1130F 58 < 0.01
+ 803F 70 < 0.01
PRE 084-treated � 1143F 16 < 0.01
+ 740F 124 < 0.01
a Mice were pretreated 5 days per week for 2 weeks with saline
(control), cocaine (5 mg/kg), or PRE 084 (20 mg/kg), implanted with 105
LIC2 tumor cells by subcutaneous injection, and then continued on drug
B. Gardner et al. / Journal of Neuroimmunology 147 (2004) 95–9896
1991). Thus, sigma ligands such as cocaine might pro-
mote a Th2 type immune response capable of regulating
immune function in vivo. To investigate this hypothesis,
we evaluated the capacity for both cocaine and another
well-characterized sigma ligand to regulate antitumor
immunity, cytokine production, and tumor growth in vivo
in a murine tumor model. These studies reveal that
cocaine, acting via a sigma1 receptor pathway, modulated
the balance of T helper type 1 (Th1) and type 2 (Th2)
cytokines, suppressed antitumor immune responses and,
as a consequence of these effects, enhanced the rate of
tumor growth.
treatment.b Mice were either pretreated with BD1047 (20 mg/kg) or saline prior to
each injection of drug.c Tumor size was measured at 21 days after tumor implantation and
volume recorded from measurement with calipers in three dimensions.d P value comparing treatment group to control animals receiving saline
alone or treatment groups compared to treatment plus BD 1047. N = 6 per
group.
2. Results and discussion
2.1. Sigma1 receptor agonists promote tumorigenicity in
immunocompetent mice
To determine how sigma1 receptor agonists modulate
tumor growth, we evaluated their effects on the growth of
weakly immunogenic Line 1 alveolar cell carcinoma
(L1C2, H-2d) cells in vivo in BALB/c mice. Before
implantation of tumors, mice were pretreated for 2 weeks
with intraperitoneal injections of cocaine (5 mg/kg,
obtained from NIDA), a selective sigma1 receptor agonist,
PRE 084 (20 mg/kg; TOCRIS Cookson, Ellisville, MO),
or diluent control (saline) five times per week. L1C2
tumor cells (105) were then inoculated subcutaneously
and tumor growth over time was compared in mice
receiving continued injections with cocaine or PRE 084
as compared that observed in diluent-treated controls.
There was a significant enhancement of L1C2 tumor
growth in mice treated with PRE 084 or cocaine,
compared to control mice. The cocaine-mediated increase
in tumor growth was sigma receptor-dependent as dem-
onstrated by treatment with BD1047 (20 mg/kg; TOCRIS
Cookson), a sigma receptor antagonist that abrogated the
increase in tumor growth (Table 1). Treatment with
BD1047 alone did not alter tumor growth.
2.2. Cocaine and sigma receptor agonists regulate Th1/Th2
cytokine profiles
Prior studies demonstrated that sigma1 receptor ligands
modulate cell-mediated immune responses (Wang et al.,
1994; Bourrie et al., 1995; Carayon et al., 1995; Derocq
et al., 1995; Liu et al., 1995), leading us to speculate that
treatment with sigma1 receptor ligands might act by limiting
the production of Th1 cytokines and increasing the produc-
tion of Th2 cytokines. This shift in cytokine profile can limit
effective immune responses to a tumor challenge and
thereby allow increased tumor growth. We recently reported
(Zhu et al., 2003) that cocaine treatment resulted in approx-
imately a twofold decrease in IFN-g and twofold increase in
IL-10 production at the tumor site compared to diluent
treatment. Splenocytes isolated from cocaine-treated, non-
tumor-bearing mice showed a similar shift in cytokine
pattern (Zhu et al., 2003). Thus, sigma receptor ligands
such as cocaine can result in a shift towards a Th2 dominant
immune response (Fig. 1). In addition to changes in IL-10
and IFN-g production, we found that cocaine administration
augments the production of the immune suppressive cyto-
kine TGF-h. Splenocyte TGF-h production increased two-
fold in cocaine-treated compared to diluent-treated tumor-
bearing mice (2.2 vs. 1.0 ng/ml/106 cells).
2.3. Administration of anti-IL-10 mAb prevents the cocaine
mediated increase in tumor growth in vivo
Based on the known detrimental effects of IL-10 in this
tumor model (Huang et al., 1998), we speculated that the
induction of IL-10 by sigma1 receptor ligands was respon-
sible for the observed enhancement of tumor growth in vivo.
IL-10 inhibits a broad array of immune parameters that
include antigen presentation, antigen-specific T cell prolif-
eration (de Waal-Malefyt et al., 1991; Taga and Tosato,
1992), and type 1 cytokine production (Fiorentino et al.,
1991; Mosmann and Moore, 1991). IL-10 is also a potent
inhibitor of host immunity (Rohrer and Coggin, 1995;
Sharma et al., 1999) and may act at several points to
interfere with either the generation or maintenance of
antitumor immune responses. Neutralizing anti-IL-10 mAb
was therefore administered to mice receiving PRE 084 or
cocaine in order to block the biological effects resulting
from the heightened production of IL-10. Administration of
anti-IL-10 mAb, but not control antibody, prevented these
sigma1 receptor agonists, including both cocaine and PRE
084, from increasing the rate of tumor growth.
The production of immunoregulatory cytokines is a
critical element in the generation of an effective immune
response. The tumor-bearing state is associated with an up-
Fig. 1. Cocaine or the sigma receptor agonist PRE 084 promote a Th1 cytokine profile. Mice were treated with PRE 084, cocaine or diluent control using the
dosing and injection schedule as described in the text. L1C2 tumor cells (105) were injected subcutaneously and non-necrotic tumors recovered from L1C2
tumor-bearing mice after 4 weeks of continued drug treatment. Tumors were homogenized and the concentrations of IL-10 and IFN-g in the resulting
supernatant determined by cytokine-specific ELISA (N= 6 per group). Mean values of the ratio of IFN-g to IL-10 (F S.E.M.) are shown.
B. Gardner et al. / Journal of Neuroimmunology 147 (2004) 95–98 97
regulation of immune suppressive cytokines including IL-10
and TGF-h (Alleva et al., 1994; Maeda and Shiraishi, 1996).
As a result, host immunity against tumors is down-regulated
(Huang et al., 1998). Tumors may either directly release
suppressive cytokines or orchestrate host immune cells to
produce them (Huang et al., 1998; Seo et al., 1999).
Consistent with these conclusions, we previously found that
production of IL-10 by cutaneous carcinomas provides a
mechanism for evasion of T cell immunity (Kim et al.,
1995). We also found that transgenic mice over-expressing
IL-10 under the control of the IL-2 promoter were unable to
limit the growth of immunogenic tumors (Hagenbaugh et
al., 1997). Administration of blocking IL-10 mAbs restored
in vivo antitumor responses in these transgenic mice. Our
finding that sigma1 receptor agonists, such as cocaine,
increased the release of IL-10 in vivo at the tumor site,
and increased lymphocyte IL-10 production in vitro, sug-
gested a mechanism by which these agents exaggerate
tumor-induced immune suppression and promoted tumor
growth. The capacity for anti-IL-10 mAb to reverse the
detrimental effects produced by sigma1 receptor ligands
lends strong support to this hypothesis.
These findings may have important clinical implications
for both medically prescribed drugs as well as those used in
abuse. For example, cocaine smokers have increased histo-
pathologic abnormalities in their lungs including a higher
incidence of hyperplasia and squamous cell metaplasia
compared to nonsmokers (Fligiel et al., 1997). In addition,
cocaine smokers have elevated expression of molecular
markers that are associated with increased cancer risk such
as Ki-67 and epidermal growth factor receptor (Barsky et al.,
1998). Thus cocaine smoking, like tobacco, has been impli-
cated in field cancerization of bronchial epithelial cells
(Barsky et al., 1998). These findings raise a concern that
the combination of these genetic alterations and sigma
ligand-induced immune suppression may have additive or
synergistic effects in promoting tumorigenesis. In addition,
there are epidemiological studies that associate cocaine
abuse with an increase in opportunistic infections and
progression of HIV (Chaisson et al., 1989; Caiaffa et al.,
1994). In an experimental model of AIDS, we have found
that cocaine administration significantly enhanced HIV rep-
lication (Roth et al., 2002). Further studies are warranted to
determine if immune suppression, opportunistic infections,
and cancer potentiation result from abuse of crack cocaine
and whether these in vivo effects related to activation of
sigma receptors.
Acknowledgements
This work was supported by National Institutes of Health
Grants R01 DA08254, RO1 CA71818, and P50 90388, and
the Merit Review Research Funds from the Department of
Veterans Affairs.
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