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subcutaneous inflammation [11], postoperative ileus [12], pancreatitis [13], allergic lung inflammation [14,15], and acute lung injury [16]. The agonist of nAChRs nicotine has been used in clinical trials, but its clinical potential is limited by its collateral toxicity [17].Appreciations of an important role of α7 nAChR in regulation of the immune inflammation urged a search for selective nicotinic agonists that avoid the undesired side effects of nicotine [2]. Further elucidation of the nAChR-mediated regulation of inflammation should help develop novel treatments allowing to regulate specific types of immune reactions by selectively activating or blocking particular nAChR subtypes expressed in monocytes/macrophages.Various immune cells possess diverse repertoires of nAChRs and, therefore, respond differently to the nicotinic agonists that exhibit varying affinities to distinct nAChR subtypes.The pharmacologic subtype of the ACh-gated ion channel is determined by a specific combination of the nAChR subunits forming the channel. The “muscle”-type nAChRs can be comprised by α1, β1, γ, δ, and ε subunits, and the “neuronal”-type nAChRs—by α2–α10 and β2–β4 subunits [18–21]. The α7, and α9 subunits can form homomeric nAChR channels sensitive to α-bungarotoxin (αBtx ). The heteromeric channels can be composed of α2, α3, α4,α5, α6, β2, β3 and β4 subunits, e.g., α3(β2/β4)±α5, and α9 can also form a heteromeric channel with α10 [21]. The signal transduction pathways downstream of different nAChRs may be activated by both ionic events, such as Ca 2+ influx, and changes of the stoichiometry of a multiprotein complex formed by the nAChR subunit(s) [22,23]. Therefore, a net biologic effect of ACh in a particular type of immune cell depends on the subunit composition of the major nAChR subtypes expressed by the cell at a given stage of its development and activation.The presence of nAChRs in human monocyte/macrophages was suggested by the inhibitory effect of αBtx on monocyte activation [24] and nicotine binding to the human monocytic THP-1cell line [25]. By now, it has been documented that human, murine and monkey macrophages express classic nAChR subunits [4,26,27]. Expression of α1, α7, and α10 mRNAs has been detected in human macrophages [4], whereas both bone marrow-derived dendritic cells and

macrophages from C57BL/6J mice possess mRNAs encoding the nAChR subunits α2, α5, α6,

α7, α10 and β2 [28]. Macrophages also express the muscarinic class of ACh receptors [29,

30] that can modify the cell response to auto/paracrine ACh.

The human monoblastoid tumor cell line U937 [31] that can be differentiated into macrophage-

like cells by treatment with phorbol-12-myristate 13-acetate (PMA ) exhibits ACh synthesizing

activity of choline acetyltransferase and contains approximately 0.02 pmol/106 of ACh [32].

Although, to the best of our knowledge, the subunit composition of nAChRs expressed in U937

cells have not been established, it has been reported that these cells respond to nicotine [33,

34]. Therefore, U937 cells provide a useful model for studying basic mechanisms of

macrophage regulation by auto/paracrine ACh through nAChRs.

In this study, we characterized the profile of nAChR subunits expressed in the macrophage-

like differentiated U937 cells and demonstrated how the receptor repertoire changes upon cell

activation with lipopolysaccharide (LPS ). We also established relative contributions of α7-

and non-α7 nAChR subtypes expressed in these cells to regulation of the pro- and anti-

inflammatory cytokine production. The obtained results indicated that the macrophage nAChR

subtypes are differentially coupled to regulation of production of distinct cytokines by auto/

paracrine ACh. These findings offer a new insight on how nicotinic agonists control

inflammation, thus laying a groundwork for the development of novel immunomodulatory

therapies based on the nAChR subtype selectivity of nicotinic agonists.

NIH-PA Author Manuscript

MATERIALS AND METHODS

Cells and Reagents

The human monoblastoid tumor cell line U937 was purchased from ATCC (Catalog #CRL-2367; Manassas, VA) and grown in the ATCC complete growth medium (Catalog #30-2001) at 37°C in a humid, 5% CO 2 incubator. To differentiate into macrophages, the U937cells were treated with 200 nM PMA (Sigma-Aldrich Corporation, St Louis, MO) and allowed to adhere to tissue culture plate for 3 days [35]. The nicotinic ligands epibatidine (Epi ),mecamylamine (Mec ), methyllycaconitine (MLA ) and αBtx, the inhibitor of ACh synthesis hemicholinium-3 (HC-3), and LPS were from Sigma-Aldrich Corporation. AR-R17779 was a gift from AstraZeneca Pharmaceuticals (Wilmington, DE). Particular doses of all drugs were selected based on the pilot dose-response experiments.Characterization of nAChRs Expressed in U937 Cells The profile of nAChR subunits expressed in differentiated, macrophage-like U937 cells was determined in a standard reverse-transcription PCR (RT-PCR ) assay using the published primer sets for human α1-α7, α9, α10, β1-β4, γ, δ and ε nAChR subunits (Operon, Alameda,CA) and the amplification conditions shown in Table 1. All primers were tested using normal human muscle and brain PCR ready first strand cDNAs purchased from BioChain Institute Inc. (Hayward, CA) [36]. To control for contamination of DNase-treated samples with residual genomic DNA, the reverse transcription step was omitted.Real-time Quantitative Polymerases Chain Reaction (qPCR) Experiments Total RNA was extracted from U937 cells at the end of exposure experiments with the RNeasy Mini Kit (Qiagen, Valencia, CA) and used in the qPCR assay detailed elsewhere [37]. All qPCR primers were designed with the assistance of the Primer Express software version 2.0computer program (Applied Biosystems, Foster City, CA) and the service Assays-on-Demand

provided by Applied Biosystems. The qPCR reactions were performed using an ABI Prism

7500 Sequence Detection System (Applied Biosystems) and the TaqMan Universal Master

Mix reagent (Applied Biosystems) in accordance to the manufacturer’s protocol, as described

by us in detail elsewhere [38]. To correct for minor variations in mRNA extraction and reverse

transcription, the gene expression values were normalized using the housekeeping gene

glyceraldehyde-3-phosphate dehydrogenase. The data were analyzed with a sequence detector

software (Applied Biosystems) and expressed as mean ± standard deviation of mRNA in

question relative to that of control.

In-cell Western (ICW) Assay

The ICW assay was performed as described by us in detail elsewhere [39], using the reagents

and equipment from LI-COR Biotechnology (Lincoln, NE). After incubation of 3×104 U937

cells/well of a 96-well plate in the growth medium with or without test agents for 16 h, the

experimental and control U937 cells were fixed in situ , washed, permeabilized with Triton

solution, incubated with the LI-COR Odyssey Blocking Buffer for 1.5 h and then treated

overnight at 4°C with a primary mouse antibody to human IL1-β, IL-6, IL-10 or IL-18, TNF-

α (R&D Systems, Minneapolis, MN). After that, the cells were washed, and stained for 1 h at

room temperature with a secondary LI-COR IRDye 800CW anti-mouse antibody diluted 1:800.

Sapphire700 (1:1000) was used to normalize for cell number/well. The protein expression was

then quantitated using the LI-COR Odyssey Imaging System.

NIH-PA Author Manuscript

Statistical Analysis

All experiments were performed in duplicates or triplicates, and the results were expressed as

mean ± standard deviation. Statistical significance was determined using Student’s t -test.

Differences were deemed significant if the calculated p value was <0.05.RESULTS The nAChR Subunits Expressed in U937 Cells The RT-PCR experiments using previously characterized human nAChR subunit gene-specific primers (Table 1) and PMA-differentiated U937 cells revealed the expression of α1, α4, α5,α6, α7, α9, α10, β1, β2, β3 and β4 subunits (Fig. 1A). The products were not amplified from putative contaminating DNA. These results indicated that the macrophage-like U937 cells express both the muscle (i.e., α1 and β1 containing)- and the neuronal (i.e., α4-, α6-, α9- and α7-made) subtypes of nAChRs. The homomeric ACh-gated ion channels in these cells can be comprised by several α7, and α9 subunits, and the heteromeric channels—by α9 plus α10subunits as well as a combination of several other nAChR subunits found in these cells.Activation of Differentiated U937 Cells Alters the Profile of their nAChR Subunits Using qPCR, we found that stimulation of PMA-pretreated U937 cells for 16 h with 200 ng/ml LPS altered expression of the genes encoding different nAChR subunits, suggesting reciprocal changes in the structure and function of the channels formed. Compared to unstimulated U937 cells, the relative amount of mRNA encoding α1, α4, α5, α7, α10 and β1subunits increased, that encoding α6 and β2 subunits decreased, and the relative quantity of α9, β3 and β4 mRNAs did not change significantly (Fig. 1B). Notably, the major increase was observed for α1 and β1 mRNAs (approximately 15-fold), as well as α5 and α7 mRNAs (approximately 7-fold). Because the initial levels of α1, β1 and α7 subunits appeared to be rather low (Fig. 1A), both the muscle-type and the α7-containing nAChR subtypes seem to be

the most sensitive to induction by LPS. An increase of α5 and α10 subunits indicates that the

subunit composition of constitutively expressed nAChRs becomes enriched with the non-ACh-

binding subunits forming α4β3α5 and α9α10 nAChR channels. Activation of U937 cells

appeared to be associated with a decrease of channels comprised by α6 and β2 subunits.

Nicotinic Effects on the LPS-induced Production of Pro-inflammatory Cytokines

The role of nAChRs in regulation of the inflammatory cytokine production was investigated

in differentiated U937 cells stimulated with LPS in the presence or absence of nAChR ligands.

Previous studies have demonstrated that LPS upregulates production of inflammatory

cytokines by PMA-pretreated U937 cells [40], and that nicotine can inhibit this effect [33]. To

elucidate the role of individual nAChR subtypes in mediating the reported anti-inflammatory

action of nicotinic agonists on monocyte/macrophages, we exposed U937 cells to 200 ng/ml

LPS in the absence (control) or presence of 1 μM agonist Epi that can activate all nAChR

subtypes expressed in these cells [41,42]. As expected, Epi significantly inhibited expression

of the genes encoding the inflammatory cytokines TNF-α, and IL-1β, both at the transcriptional

and translational levels, and IL-6 and IL-18—at the protein level (Fig. 2). The dose responses

were performed to examine the effects of Epi on the above cytokines at the protein levels. The

results demonstrated the dose-dependent inhibition of the levels of TNF-α, IL-1β, IL-6 and

IL-18 proteins in differentiated U937 cells stimulated with LPS in the presence of increasing

concentrations of Epi (Fig. 2C). To evaluate possible contribution of distinct nAChR subtypes

to the inhibitory action of Epi on production of inflammatory cytokines, the cells were exposed

to this agonist in the presence of 50 μM of Mec, which inhibits all neuronal nAChR subtypes,

or 1 μM of αBtx, which binds to and inhibits both the muscle-type nAChR and the homomeric

neuronal-type nAChR channels [41,43–46]. Each antagonist abolished the inhibitory effects

NIH-PA Author Manuscript

of Epi with a slightly distinctive efficacy, and changes in gene expression at the mRNA vs.

protein levels somewhat differed (Fig. 2). Both at the mRNA and the protein levels, the

expression of the TNF-α gene was altered predominantly through the αBtx-sensitive nAChRs

(p<0.05). Both the Mec- and αBtx-sensitive nAChRs regulated expression of the IL-1β mRNA

and protein equally efficiently (p<0.05). The alterations of IL-6 and IL-18 expression were

observed only at the protein level and were primarily induced through the Mec-sensitive

nAChRs (p<0.05).

These results suggested that the macrophage nAChR subtypes are differentially coupled to

regulation of production of pro-inflammatory cytokines.

Regulation of IL-10 Production

Since it has been documented that human monocytes and differentiated, macrophage-like U937

cells produce IL-10, which can be upregulated by LPS as well as agonists of cellular receptors

to cytotransmitters and endocrine hormones [47–49], we next measured nicotinic effects on

the expression of the IL-10 gene in PMA-pretreated U937 cells stimulated by LPS. As expected

from previous reports, LPS increased the relative amounts of IL-10 mRNA and protein (Fig.

3A,B). Epi significantly (p<0.05) upregulated expression of the IL-10 gene at the translational

level only. The effect of Epi was dose-dependent (Fig. 3C). Both Mec and MLA completely

abolished the Epi-depended upregulation of IL-10 (p<0.05).

Since it has been previously reported that α7 nAChR expressed in macrophages and dendritic

cells predominantly mediates the anti-inflammatory action of ACh [4,16], we sought to identify

the role of this receptor in the cholinergic control of IL-10 production. To selectively activate/

inactivate the α7-made nAChR we exposed differentiated U937 cells to LPS in the presence

of the increasing concentrations of the α7-selective agonist AR-R17779. The IL-10 production

was upregulated in a dose-dependent fashion (Fig. 3C). The cells exposed to LPS in the

presence of 50–100 μM AR-R17779 showed approximately 2.5-fold increase of IL-10

production that significantly (p<0.05) exceeded Epi-induced upregulation (Fig. 3A,B). To

confirm the receptor specificity of AR-R17779 action, we incubated cells with AR-R17779,

100 μM, in the presence or absence of the α7-preferring antagonist MLA, 100 nM [44,50] that

completely abolished effect of the agonist (Fig. 3A,B).

These findings indicated that upregulation of IL-10 production in macrophages by auto/

paracrine ACh is mediated predominantly through α7 nAChR.

The Role of Auto/paracrine ACh in the Nicotinic Anti-inflammatory Pathway

Since U937 cells synthesize ACh [32], we used these cells as a model-system to investigate

relative contribution of auto/paracrine ACh to the nicotinic anti-inflammatory pathway. In this

series experiments, 1 h prior to addition of LPS, the cultures of PMA-differentiated U937 cells

were fed with the medium containing 20 μM of the metabolic inhibitor of ACh synthesis HC-3

[51,52]. By both qPCR and ICW, the level of IL-10 gene expression in the HC-3 treated cells

decreased by approximately 5-fold (Fig. 4). If the HC-3 pretreated cells were stimulated with

LPS in the presence of Epi, which could substitute ACh at the nAChR binding site, the IL-10

production increased and approached the control levels determined in the cells exposed to LPS

without test drugs. Thus, elevation of IL-10 by Epi in the presence of HC-3 apparently occurred

because the exogenously added agonist exhibited an ACh-like effect by activating nAChRs.

This effect of Epi could be abolished by both Mec and MLA, with the latter antagonist

exhibiting a significantly (p<0.05) higher efficiency (Fig. 4).NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

These results indicated that the cholinergic control of inflammation due to upregulation of

IL-10 production through the α7-coupled pathway may represent a common mechanism of

anti-inflammatory action of non-neuronal ACh.

DISCUSSION It has become increasingly clear that in addition to its well known function as a neurotransmitter, ACh plays a much wider role in life being ubiquitously expressed in various cells and organisms and coupled to regulation of a large variety of biological processes [53,54]. The ACh regulatory axis, which is comprised by the cholinergic enzymes and receptors,choline high-affinity transporter and vesicular ACh transporter, has been found to play an important role in mediating host responses to environmental stimuli, including the immune response [55,56]. Recent research has convincingly demonstrated that the nicotinic arm of the regulatory ACh axis in immune cells is coupled to the physiologic control of T- and B-lymphocyte survival and function [57,58].In this study, we used the macrophage-like U937 cells to elucidate the mechanisms of the physiologic control of cytokine production by auto/paracrine ACh through the nicotinic class of ACh receptors expressed in these cells. Both the muscle- and the neuronal-types of nAChRs were found to be expressed in differentiated U937. The repertoire of the receptors changed upon cell stimulation with LPS. Distinct nAChR subtypes showed differential regulation of the production of pro- and anti-inflammatory cytokines. The IL-10 gene expression was altered due to inhibition of endogeneous ACh production, indicating that the auto/paracrine ACh plays an important role in the physiologic control of macrophage function during the immune inflammation.The cholinergic (nicotinic) anti-inflammatory pathway [3–5,59,60] is a physiologic (neuro)immune mechanism that regulates innate immune function and controls inflammation. The functional activity of this pathway can be modulated through both neuronal and non-neuronal

cholinergic components, such as efferent vagal neurons and macrophage nAChRs,

respectively. The outcome of pharmacologic stimulation of the nicotinic anti-inflammatory

pathway, however, may be either beneficial and harmful. On the one hand, the nicotinic

agonists have already been successfully used to treat various in vitro and in vivo models of

inflammation (reviewed in [61]). On the other hand, nicotine and cigarette smoke cause

alterations of the innate defense mechanisms and immune surveillance due to changes in local

cytokine environment and functional impairment of the monocyte/macrophage and dendritic

cell systems [62–68]. It has been documented that nicotine: (i) lowers endocytosis and

phagocytosis of human monocyte-derived dendritic cells and decreases the levels of IL-12

[67]; (ii) reduces cytokine release from LPS-stimulated human leukemia peripheral blood

monocyte cells [69] and human monocytes [70]; (iii) reduces TNF-α release and expression

of TNF-α mRNA in murine alveolar macrophage cell line [14]; (iv) downregulates IL-1β

production by human peripheral blood monocytes [71]; and (v) inhibits the LPS-induced IL-1

and IL-8 expression at the transcriptional level in the U937 cells [33]. This cell line was used

in this study as an in vitro model system for nicotinic regulation of cytokine production by

macrophages. Indeed, experiments with U937 cells have limitations, as the monocytic cell lines

do not often mimic data obtained from primary cells and importantly, in vivo situations.

Therefore, future studies should determine if the nicotinic effects on cytokine production

observed by us in the present study can be replicated with normal macrophages.

Our results demonstrated for the first time the complete profile of nAChRs expressed by U937

cells, and revealed changes in the repertoire of the nAChR subunits upon cell activation of with

LPS. The fact that activation of U937 cells with LPS produced a dramatic change in the levels

of expression of the nAChR subunit genes is not surprising. It has been documented that

NIH-PA Author Manuscript

mammalian cells change the repertoire of their nAChRs during differentiation and upon environmental stimulation [38,78–82]. Recent analysis of the biologic effects of macrophage nAChRs through microarray analysis of nicotine-induced changes in gene expression in U937cells revealed that 118 genes are up-regulated and 97 down-regulated [34].While expression of both α7 and non-α7 nAChRs was affected by LPS stimulation, the present study was focused on the anti-inflammatory function of ACh mediated by the α7-coupled pathway, in keeping with the notion that the ACh-gated ion channels comprised by α7 subunits are coupled to suppression of inflammation [4,70,72–74]. Noteworthy, activated U937 cells overexpressed α7. This observation, taken together with the results of pharmacologic experiments with the α7 ligands AR-R17779 and MLA, indicated that the major contribution of the macrophage α7 nAChR to the anti-inflammatory function of auto/paracrine ACh is upregulation of IL-10 production. Hence, our rationale for measuring the effect of HC-3 on production of only IL-10, but not other cytokines, was elucidation of the role of α7 nAChR in regulation of anti-inflammatory cytokine production by ACh.The observed changes of the repertoire of nAChRs indicates that activated U937 cells express pharmacologically different receptors compared to the resting cells. It is well documented that inclusion of α5 subunits alters the properties of heteromeric nAChRs. In particular, channels containing the α5 subunits can be activated and desensitized by much lower (nanomolar)concentrations of nicotine than their non-α5-containing analogues [75]. Moreover, α5 increases the channel permeability to Ca 2+ and its sensitivity to intracellular Ca 2+, which makes heteromeric receptors formed similar to α7 nAChR homomers [76,77]. Similarly, addition of α10 subunit to α9-made homomers alters the resulting receptor sensitivity to extracellular Ca 2+ and increases its agonist-mediated desensitization [21]. Therefore, activated U937 cells appear to not only overexpress α7 nAChRs but also re-organize other nAChR subtypes, thus synergizing with the α7 function.The ability of the nicotinic agonist epibatidine to decrease pro-inflammatory cytokines is in

keeping with known immunosuppressive action of nicotine [83], and with our previous reports

about negative effect of nAChR activation on T- and B-cell functions, and antibody production

[57,58,74,84]. The Mec-sensitive nAChRs coupled to downregulation of IL-6 and IL-18

production can be the α5 containing α4 receptors, because previous studies have demonstrated

that activation of α4 nAChR in a mouse macrophage cell line produces an anti-inflammatory

response by inhibiting TNF-α, IL-6, and IL-12 production [26]. On the other hand, since

upregulation of the genes encoding α1 and β1 subunits by LPS considerably exceeded that of

α7, one may speculate that the muscle-type macrophage nAChR also plays an important role

in the anti-inflammatory action of nicotinic agonists mediated by downregulation of pro-

inflammatory cytokines.

The knowledge about coupling of distinct nAChR subtypes to selective regulation of

production of pro- and anti-inflammatory cytokines may be exploited for the development of

novel therapeutic strategies allowing to achieve either immunosuppression or

immunostimulation, depending on the receptor selectivity of the nicotinic agonist used. In

addition to being pro-inflammatory, the studied cytokines can exert substantial effects on innate

and adaptive immunity. In particular, IL-1, IL-6 and TNF-α are co-stimulatory for T and B

lymphocytes; IL-6 drives proliferation and differentiation of B-cells into antibody-secreting

cells, whereas IL-18 is a potent activator of natural killer cells and a stimulator of the Th2

response [85].

In conclusion, results of the present study identified the major macrophage nAChR subtypes

that can mediate the physiologic control of cytokine production by auto/paracrine ACh, and

pointed out an important role of the macrophage ACh regulatory axis in the immune

NIH-PA Author Manuscript

inflammation. Our observations of the differential control of inflammation by ACh through

α7 and non-α7 nAChRs expand the current knowledge about the “cholinergic anti-

inflammatory pathway”. The unique coupling of macrophage nAChR subtypes to regulation

of specific pro- and anti-inflammatory cytokines can diversify the immunoregulatory effects

of ACh, thus allowing this auto/paracrine cytotransmitter to coordinate the immune response

to a specific environmental stimulus. The muscle- and the neuronal-types of the macrophage

nAChRs that regulate cytokine production are potential targets for the pharmacologic

regulation of inflammation. The pharmacologic regulation of inflammation outside the central

nervous system may be achieved by using nicotinic agents with poor or no permeability of the

blood-brain barrier. Future studies should be focused on the nAChR subtypes that appear to

mediate the immunomodulatory effects of ACh on monocyte/macrophages.Acknowledgments This work was supported by the NIH grants GM62136, DE14173 and ES014384, and research grants from the Institute for Science and Health (to S.A.G.), and Philip Morris USA Inc. and Philip Morris International (to M.V.S).References 1. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 2005;4:673–84. [PubMed: 16056392]2. Ulloa L, Wang P. The neuronal strategy for inflammation. Novartis Found Symp 2007;280:223–33.discussion 33–7. [PubMed: 17380797]3. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N,Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–62. [PubMed: 10839541]4. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Yang H, Ulloa L, Al-Abed Y,Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8. [PubMed: 12508119]

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NIH-PA Author Manuscript

Figure 1. PCR analysis of nAChR subunit expression in differentiated U937 cells

A. Expression of nAChR subunits in the U937 cells pretreated with 200 nM PMA was analyzed

by RT-PCR using published primers (Table 1). Left lane is a 100 bp molecular weight ladder.

B. qPCR was performed after 16 h of incubation of differentiated U937 cells with 200 ng/ml

LPS in a humid, 5% CO 2 incubator at 37°C, as detailed in the Materials and Methods section.

The results are expressed as fold of control determined in control PMA-differentiated U937

cells, and taken as 1. Asterisk = p<0.05 compared to control.

NIH-PA Author Manuscript

Figure 2. Nicotinic effects on inflammatory cytokine production by LPS-stimulated U937 cells

A, B. Differentiated U937 cells, 1×106 cells/well, were incubated for 16 h in a humid, 5%

CO 2 incubator with 200 ng/ml LPS in the absence or presence of 1 μM Epi ± 50 μM Mec or

1 μM αBtx, after which the expression of the genes encoding TNF-α, IL-1β, IL-6 and IL-18 at

the mRNA and protein levels was measured by qPCR (A ) and ICW (B ), respectively, as detailed

in Materials and Methods. Asterisk = p<0.05 compared to LPS given alone; pound sign =

p<0.05 compared to Epi given alone.

C. The dose-dependent inhibition of the levels of TNF-α, IL-1β, IL-6 and IL-18 proteins in

differentiated U937 cells stimulated with LPS in the presence of increasing concentrations of

Epi.

The results are expressed as fold of control determined in control PMA-differentiated U937

cells, and taken as 1.

NIH-PA Author Manuscript

Figure 3. Nicotinic effects on IL-10 production by LPS-stimulated U937 cells A, B. Differentiated U937 cells were stimulated with LPS in the presence or absence of 1 μM Epi ± 50 μM Mec or 100 nM MLA, or 100 μM AR-R17779 (AR ) ± 100 nM MLA and used in the qPCR (A ) and ICW (B ) assays of the IL-10 gene expression as described in the legend to Fig. 2. Asterisk = p<0.05 compared to LPS given alone; pound sign = p<0.05 compared to the relevant agonist given alone.C. Concentration-dependent effects of Epi and AR-R17779 on the level of IL-10 protein in differentiated U937 cells stimulated with LPS.The results are expressed as fold of control determined in control PMA-differentiated U937

cells, and taken as 1.

NIH-PA Author Manuscript

Figure 4. Assessment of contribution of auto/paracrine ACh to the nAChR-mediated upregulation of IL-10 production Differentiated U937 cells, 1×106 cells/well, were preincubated for 1 h with 20 μM HC-3 in a humid, 5% CO 2 incubator, after which, the cells were exposed without washing to 200 ng/ml LPS and 1 μM Epi ± 50 μM Mec or 100 nM MLA, and used in the qPCR and ICW assays of IL-10 gene expression, as detailed in Materials and Methods. The dose of Epi used in this experiment was chosen based on the dose response curve for Epi shown in the panel “C” of Fig. 3, since in both experiments Epi was used to upregulate IL-10. The results are expressed as fold of control determined in PMA-differentiated U937 cells without stimulation with LPS or test drugs, and taken as 1. Plus sign = p<0.05 compared to control; asterisk = p<0.05compared to LPS given alone; pound sign = compared to HC-3 given alone.

NIH-PA Author Manuscript

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Table 1

Primers used for RT-PCR analysis of nAChRs in differentiated U937 cells*

Target mRNA Forward/reverse primers Product size, bp Anneal temperature Sources α1CGT CTG GTG GCA AAG CT

CCG CTC TCC ATG AAG TT

58055[86]

α2GGA GCT CTG CCA CCC CCT AC

AAC ATA CTT CCA GTC CTC

32764[87]

α3CTG GTG AAG GTG GAT GAA GT

CTC GCA GCA GTT GTA CTT GA

46458[86]

α4GGA TGA GAA GAA CCA GAT GA

CTC GTA CTT CCT GGT GTT GT

44458[86]

α5TCA ACA CAT AAT GCC ATG GC

CCT CAC GGA CAT CAT TTT CC

21964[87]

α6GTG GCC TCT GGA CAA GAC AA

AAT TAT AAA TAC CCA AAG A

37258[86]

α7CTT CAC CAT CAT CTG CAC CAT

GGT ACG GAT GTG CCA AGG

ATA T

30855[87]

α9GTC CAG GGT CTT GTT TGT

ATC CGC TCT TGC TAT GAT

40358[87]

α10CTC TCA AGC TGT TCC GTG ACC

AAG GCT GCT ACA TCC ACG C

39464[88]

β1TGT ACC TGC GTC TAA AAA GG

GCA GGT TGA GAA CCA CGA CA

45560[87]

β2CAG CTC ATC AGT GTG CA

GTG CGG TCG TAG GTC CA

34758[89]

β3AGA GGC TCT TTC TGC AGA

GCC ACA TCT TCA AAG CAG

35460[89]

β4GTG AAT GAG CGA GAG CAG AT

GGG ATG ATG AGG TTG ATG GT

52458[86]

δCAG ATC TCC TAC TCC TGC AA

CCA CTG ATG TCT TCT CAC CA

47158[86]

γCGC CTG CTC TAT CTC AGT CA

GGA GAC ATT GAG CAC AAC CA

54656[86]

εGTA ACC CTG ACG AAT CTC AT

GTC GAT GTC GAT CTT GTT GA

43255[86]

All products were sequenced by the designers of the PCR primer used in this study.

2020年湖南省郴州市高考生物三模试卷 (含答案解析)

2020年湖南省郴州市高考生物三模试卷一、单选题（本大题共6小题，共36.0分） 1.下列对处于不同免疫状态的小鼠分析合理的是（） A. 吞噬细胞缺陷的小鼠特异性免疫无法产生 B. 胸腺被破坏的小鼠因无淋巴因子产生，无体液免疫 C. 骨髓被破坏的小鼠输入造血干细胞后能恢复体液免疫和细胞免疫 D. B淋巴细胞缺陷的小鼠虽无法合成抗体，但仍能对结核杆菌产生免疫反应 2.自由基学说认为，自由基能攻击和破坏细胞内多种执行正常功能的生物分子，最终致使细胞衰老。下列有关自由基的说法错误的是（） A. 攻击蛋白质降低某些酶的活性 B. 攻击DNA可能引发基因突变 C. 攻击磷脂直接导致中心体损伤 D. 攻击生物膜引发新的自由基产生 3.植株甲是二倍体水稻，利用植株甲获得了植株乙，然后利用植株甲和乙又获得植株丙和丁。培养过程如图所示。下列有关叙述正确的是（） A. 用秋水仙素处理植株甲的雌蕊柱头可获得植株乙 B. 植株丙与植株丁的体细胞中染色体组的数目相同 C. 获得植株丙和植株丁的过程都要经过减数分裂 D. 植株丁的花药离体培养可得到植株丙 4.如图表示乙酰胆碱（兴奋性神经递质）释放与作用机制，下列叙述错误的是（） A. 突触小泡避免乙酰胆碱被细胞内酶破坏 B. 乙酰胆碱持续作用于突触后膜的受体 C. 乙酰胆碱与受体结合引发离子通道的开放 D. 乙酰胆碱的释放体现了细胞膜的结构特点 5.下列关于“探索生长素类似物促进插条生根的最适浓度实验”的叙述，错误的是（）

A. 实验中应设置一组用蒸馏水处理的插条作为对照组 B. 用不同浓度的生长素类似物溶液浸泡插条基部是为了控制自变量 C. 实验中因变量可用观察统计每组插条生根的数目表示 D. 通过预实验摸索大致浓度范围是为了避免无关变量的干扰 6.如图为某家族遗传病的系谱图，己知Ⅱ-3的妻子，和Ⅱ-5的丈夫不携带该病的致病基因，且该病在群体中的发病率为1：10000．下列说法错误的是（） A. 这种遗传病是常染色体隐性遗传病 B. 若Ⅲ-5和Ⅲ-6近亲婚配，子代患病概率为1 24 C. Ⅲ-1与正常女性婚配子代患病概率为1 202 D. Ⅰ-1、Ⅰ-2、Ⅲ-1、Ⅲ-2-定是杂合子二、探究题（本大题共5小题，共60.0分） 7.作物与光合作用如图是无籽西瓜叶片净光合速率Pn（以CO2吸收速率表示）与胞间CO2浓度（Ci）的日变化曲线，据图回答下列问题：（1）胞间CO2进入叶绿体内参与______循环。（2）在9：00至11：00之间，净光合速率Pn升高，此阶段发生的变化还有______。 A．经气孔释放的CO2增多B．单个叶绿素A分子的氧化性不断增强

麻醉药理学作用于胆碱受体的药物(8.6)--作用于胆碱受体的药物习题

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第一章细胞的基本功能 1．细胞膜脂质双分子层中，镶嵌蛋白的形式：E A．仅在内表面B．仅在外表面 C．仅在两层之间D．仅在外表面与内面 E．靠近膜的内侧面，外侧面，贯穿整个脂质双层三种形式均有 2．细胞膜脂质双分子层中，脂质分子的亲水端：D A．均朝向细胞膜的内表面 B．均朝向细胞的外表面 C．外层的朝向细胞膜的外表面，内层的朝向双子层中央 D．都在细胞膜的内外表面E．面对面地朝向双分子层的中央 3．人体O2．CO2进出细胞膜是通过：A A．单纯扩散B．易化扩散C．主动转运D．入胞作用E．出胞作用 4．葡萄糖进入红细胞膜是属于：C A．主动转运B．单纯扩散C．易化扩散D．入胞作用E．吞饮 5．安静时细胞膜内K+向膜外移动是由于：B A．单纯扩散B．单纯扩散．C．易化扩散D．出胞作用E．细胞外物入胞作用6．以下关于细胞膜离子通道的叙述，正确的是：C A．在静息状态下，Na+K+通道都处于关闭状态 B．细胞受刺激刚开始去极化时,就有Na+通道大量开放 C．在动作电位去极相，K+通道也被激活，但出现较慢 D．Na+通道关闭，出现动作电位的复极相E．Na+、K+通道被称为化学依从性通道7．在一般生理情况下，每分解一分子ATP，钠泵运转可使:D A．2个Na+移出膜外B．2个K+移人膜内 C．2个Na+移出膜外，同时有2个K+移人膜内 D．3个Na+移出膜外，同时有2个K+移人膜内 E．2个Na+移出膜外，同时有3个K+移人膜内 8．细胞膜内外正常的Na+和K+浓度差的形成和维持是由于；D A．膜在安静时对K+通透性大 B．膜在兴奋时对Na+通透性增加 C Na+，K+易化扩散的结果 D．膜上Na+—K+泵的作用

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D.解救有机磷农药中毒 E.治疗室上性心动过速 5、对于ACh，下列叙述错误的是： A.激动M、N-R B.无临床实用价值 C.作用广泛 D.化学性质稳定 E.化学性质不稳定 6、与毒扁豆碱相比，毛果芸香碱不具备哪种特点？ A.遇光不稳定 B.维持时间短 C.刺激性小 D.作用较弱 E.水溶液稳定 7、切除支配虹膜的神经（即去神经眼）后再滴入毛果芸香碱，则应： A.扩瞳 B.缩瞳 C.先扩瞳后缩瞳 D.先缩瞳后扩瞳 E.无影响 8、小剂量ACh或M-R激动药无下列哪种作用： A.缩瞳、降低眼内压 B.腺体分泌增加 C.胃肠、膀胱平滑肌兴奋 D.骨骼肌收缩

E.心脏抑制、血管扩张、血压下降 9、与毛果芸香碱相比，毒扁豆碱用于治疗青光眼的优点是： A.作用强而久 B.水溶液稳定 C.毒副作用小 D.不引起调节痉挛 E.不会吸收中毒 10、可直接激动M、N-R的药物是： A.氨甲酰甲胆碱 B.氨甲酰胆碱 C.毛果芸香碱 D.毒扁豆碱 E.加兰他敏 B型题问题11～13 A.激动M-R及N-R B.激动M-R C.小剂量激动N-R，大剂量阻断N-R D.阻断M-R和N-R E.阻断M-R 11、ACh的作用是： 12、毛果芸香碱的作用是： 13、氨甲酰胆碱的作用是：问题14～15 A.用于青光眼和虹膜炎

药理学—— 胆碱受体激动药和作用于胆碱酯酶药知识点归纳

药理学——胆碱受体激动药和作用于胆碱酯酶药知识点归纳拟胆碱药可分为：一、胆碱受体激动药： 1.M、N受体激动药：【乙酰胆碱（Ach）的药理作用】

2.M 受体激动剂：【毛果芸香碱的药理作用、临床应用和不良反应】有关毛果芸香碱的叙述，错误的是 A.能直接激动M受体，产生M样作用 B.可使汗腺和唾液腺的分泌明显增加 C.常用制剂为1%滴眼液 D.可用于治疗青光眼 E.可使眼内压升高『正确答案』E 毛果芸香碱缩瞳作用的机制是 A.阻断M受体，使瞳孔括约肌松弛 B.激动M受体，使瞳孔括约肌收缩 C.激动α受体，使瞳孔扩大肌收缩 D.阻断α受体，使瞳孔扩大肌松弛 E.激动β受体，使瞳孔扩大肌收缩『正确答案』B

眼的调节

二、作用于胆碱酯酶药（一）抗胆碱酯酶药：抑制AChE的活性，致使ACh不能被水解而大量堆积，从而激动M受体和N受体，产生M样作用和N样作用。 1.易逆性胆碱酯酶抑制剂【体内过程】季铵类化合物，不易穿过血脑屏障和血眼屏障。【新斯的明的药理作用、临床应用和不良反应】新斯的明的药理作用特点是 A.兴奋骨骼肌作用最强 B.兴奋胃肠平滑肌作用最强 C.促进腺体分泌作用最强 D.兴奋中枢作用最强 E.抑制心脏作用最强『正确答案』A

『答案解析』新斯的明对骨骼肌的N2受体既有间接作用，又有直接作用。新斯的明治疗重症肌无力的机制是 A.兴奋大脑皮质 B.激动骨骼肌M胆碱受体 C.促进乙酰胆碱合成 D.抑制胆碱酯酶和激动骨骼肌N2胆碱受体 E.促进骨骼肌细胞Ca2＋内流『正确答案』D 新斯的明过量可致 A.中枢兴奋 B.中枢抑制 C.胆碱能危象 D.窦性心动过速 E.青光眼加重『正确答案』C 【其他药物】毒扁豆碱也称依色林，可透过血脑屏障，对外周和中枢都有较强的作用。眼内局部应用时，作用类似于毛果芸香碱，但较强而持久。对睫状肌作用强，容易出现头痛、眼瞳视力模糊。临床主要为局部用于治疗急性青光眼，起效较快，刺激性亦较强，长期给药时，患者不易耐受，可先用本品滴眼数次，后改用匹鲁卡品维持疗效。 2.难逆性抗胆碱酯酶药：【种类】敌百虫敌敌畏马拉硫磷对硫磷内吸磷乐果【毒理】有机磷＋胆碱酯酶=磷酰化胆碱酯酶复合物（不可复活） →老化！【中毒表现】M 样症状→轻度中毒 M ＋ N样症状→中度中毒 M ＋ N ＋中枢症状→重度中毒

气道乙酰胆碱释放机制及其受体表达

气道乙酰胆碱释放机制及其受体表达 1 序言气道胆碱能系统（Cholinergic system）在调节气道平滑肌的张力方面发挥重要作用，且与一系列的生理病理反应有关。乙酰胆碱（ACh）的合成，在神经和非神经系统可能是不同的。在神经节的传递和效应器的连接处，ACh是经典的神经递质［1］。有充分的证据表明，ACh可以从许多非神经细胞合成和释放，在这些细胞上有烟碱型（N）和毒蕈碱型（M）两种胆碱受体［2］，这些细胞可以作为ACh的靶目标。本文将综述气道胆碱能系统的释放和功能，描述胆碱受体及它们的信号系统。 2 ACh-神经递质和旁分泌介质 2.1 神经性ACh的合成和释放在自主神经节前和副交感神经节后的胆碱能神经末端，通过特定的高亲和力胆碱转运体（ChT1）在细胞外转运吸收胆碱到细胞内，乙酰辅酶A和胆碱（choline）在胆碱乙酰转移酶（ChAT）的作用下合成ACh［3］。然后通过囊胞ACh转运体(V AChT)，在跨囊胞质子梯度作用下在突触囊胞中聚集［4］。最后，去极化导致的钙离子内流引起ACh的释放。释放的ACh可以和靶细胞上的受体结合（结后受体），同时和胆碱能神经末端的自身受体结合（结前的自身受体）。ACh被胆碱酯酶（AChE）分解，作用中止。在胆碱能神经附近不论是在结前还是在结后，都有胆碱酯酶的高度表达。副交感神经节后末端存在释放ACh抑制性和兴奋性的自身受体。其中有抑制性的M 2毒蕈碱自身受体、α 2肾上腺素受体、前列腺素类EP 3受体、内皮素1受体、μ阿片受体和大麻素受体。兴奋性的有β 2肾上腺素受体和速激肽NK 2受体。β 2肾上腺素受体介导的兴奋可能是通过激活腺苷酸环化酶（AC），另外磷酸二酯酶抑制剂（ADEI）也能够促进气道副交感神经的ACh的释放。一氧化氮（NO）在气道副交感神经纤维ACh的释放表现出双重作用，小量的直接抑制作用被间接的神经激肽兴奋效果所掩盖［1］。 2.1.1 ACh释放障碍证据表明抑制性毒蕈碱M 2自身受体功能异常导致了ACh的释放增加，使迷走神经介导支气管收缩反射加强，常见于过敏原接触后。活化的嗜酸性粒细胞释放阳离子蛋白，特别是主要的碱性蛋白（MBP），可以导致毒蕈碱M 2受体功能异常。哮喘患者的嗜酸性粒细胞阳离子蛋白增加。

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胆碱受体激动剂

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(医疗药品)药理学讲稿之第六章胆碱受体激动药和作用于胆碱酯酶药

第六章胆碱受体激动药和作用于胆碱酯酶药第一节胆碱受体激动药胆碱受体激动药：可与胆碱受体结合，激动受体，产生与递质乙酰胆碱相似的作用。按其对受体亚型的选择性分三种：1、M、N胆碱受体激动药；2、M胆碱受体激动药；3、N胆碱受体激动药；一、M、N胆碱受体激动药既可兴奋M受体，产生M样作用，也可兴奋N受体，产生N样作用。（一）乙酰胆碱：胆碱能神经递质 1、性质：（1）季胺类化合物，化学性质不稳定，遇水易分解，脂溶性低；（2）作用专一性差，副作用多，体内易被ACHE分解——工具药——无临床应用价值。讲这个药的目的：有利于学习和掌握胆碱受体激动药和阻断药的药理 2、药理作用：（1）M样作用：小剂量iv便可能性产生与兴奋胆碱能神经节后纤维相似的作用表现：心率↓，血管扩张、血压下降、支气管和胃肠道平滑肌兴奋、瞳孔缩小、腺体分泌；（2）N样作用：剂量较大时，兴奋N胆碱受体——作用复杂 N2——骨骼肌兴奋； N1——交感神经节和副交感神经节兴奋，表现复杂，体内大多数器官受胆碱能和肾上腺素能神经双重支配，表现为优势效应：胃肠道、膀胱平滑肌和腺体——胆碱能优势——平滑肌兴奋，腺体分泌；

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