Expression of interleukin (IL)-12 (p40) and IL-12 (b2)

receptors in allergic rhinitis and chronic sinusitis

E. D. WRIGHT*², P. CHRISTODOULOPOULOS*, S. FRENKIEL³ and Q. HAMID*

*Meakins-Christie Laboratories, ²Department of Otolaryngology, Head and Neck Surgery, SMBD-Jewish General Hospital

and ³McGill Nasal Research Group, McGill University, Montreal, Quebec, Canada

Summary

Background Interleukin (IL)-12 is a relatively new and structurally distinct TH1-asso-

ciated cytokine produced by B cells and macrophages, which may play a suppressive role

in the development of allergic sinonasal mucosal responses.

Objective We investigated the expression of IL-12 (inducible p40 subunit) and its receptor

(IL-12R b2 subunit) in tissue biopsies of naturally exposed patients with allergy-associated

(ACS) and nonallergy-associated chronic sinusitis (NCS) and compared it with controls. We

also examined IL-12 and IL-12R expression in biopsies from a ragweed allergen challenge

model. In the allergen challenge model, the effect of pretreatment with topical cortico-

steroids on IL-12 and IL-12R expression was assessed.

Methods To detect IL-12 and IL-12R mRNA, we employed the technique of in situ

hybridization using digoxigenin-labelled riboprobes.

Results In both ACS and NCS subjects there was decreased expression of IL-12 as

compared with control (P < 0.05). IL-12R (b2) expression was decreased in ACS subjects as

compared with control (P < 0.05), however, there was no signi®cant difference found

between NCS subjects and control. In the allergen challenge subjects, there was a signi®cant

decrease in IL-12 expression following challenge (P < 0.05). This effect was abrogated by

pretreatment of the subjects with topical corticosteroids. However, IL-12R (b2) expression

showed no change following allergen challenge while pretreatment with topical cortico-

steroids resulted in increased expression of the (b2) receptor after allergen challenge

(P < 0.05).

Conclusion Our data suggest that IL-12 plays a role in the in vivo suppression of the

allergic in¯ammatory response and that the control of this suppression may be exerted

largely via the IL-12 (b2) receptor.

Keywords: allergic rhinitis, chronic sinusitis, interleukin-12 (b2) receptor, interleukin-12,

steroids

Clinical and Experimental Allergy, Vol. 29, pp. 1320±1325. Submitted 11 November 1998;

revised 15 January 1999; accepted 1 February 1999.

Introduction

Interleukin (IL)-12 is a relatively new and structurally

distinct cytokine. It is a heterodimer composed of a con-

stitutively expressed p35 subunit and a inducible p40

subunit [1,2], both of which are required for agonist

activity. IL-12 is produced by B cells and cells of mono-

cyte/macrophage lineage [1]. It is considered to be a

TH1-associated cytokine since it has been described

in vitro to stimulate TH1 differentiation, promote T-cell

production of IFNg and inhibit IgE synthesis [3,4].

In a murine model of parasitic infection, IL-12 has been

demonstrated to inhibit expression of TH2-type cytokines

[5] as well as the associated tissue eosinophilia and IgE

synthesis [6]. Further, in a murine asthma model, adminis-

tration of IL-12 reduced antigen-induced airway hyper-

responsiveness and eosinophilia [7].

Data from human subjects with allergy-associated asthma

Clinical and Experimental Allergy, 1999, Volume 29, pages 1320±1325

1320 q 1999 Blackwell Science Ltd

Correspondence: Q. Hamid, Meakins-Christie Laboratories, McGill

University, 3626 St Urbain Street, Montreal, Quebec, Canada, H2X 2P2.

showed decreased expression of IL-12 in bronchial biopsies

as compared with controls [8]. Treatment of these patients

with oral corticosteroids resulted in improved symptoms

and a reversal of their cytokine pro®le with increased

expression of IL-12 [8]. Further, in a model of human

grass pollen allergy, inhibition of the allergen-induced

late-phase skin response following successful immuno-

therapy was found to be associated with an increase in

IL-12 mRNA expression [9].

The action of IL-12 is mediated through its membrane-

bound receptor (IL-12R), which is a member of the cytokine

receptor super-family. At least two classes of IL-12R have

been described, with varying af®nity [10]. The high-af®nity

form is a heterodimer composed of b1 and b2 subunits and

is expressed on activated NK and T cells only [11]. The b1

subunit has been shown to bind IL-12 with a low af®nity

and appears only weakly capable of transmitting signalling

information, ostensibly due to its short cytoplasmic tail

which is de®cient in the tyrosine residues important in

signal transduction [10]. Functionally more important is

the b2 subunit which has a longer cytoplasmic tail that

contains the tyrosine residues whose phosphorylation is

important in signal transduction [10]. Further, it has recently

been demonstrated that commitment of TH cells to the TH2

pathway induced by IL-4 results in inhibition of IL-12Rb2

expression whereas treatment with IFNg maintained

IL-12Rb2 expression and the ability of these cells to respond

to IL-12 [12].

It thus appears that IL-12 and particularly its b2 receptor

may play a suppressive role in the development of allergic

sinonasal mucosal responses. What is lacking until now

in the literature is the direct examination of human nasal

or sinus tissue for the local expression of IL-12 and its

receptors in the sinonasal mucosa and its response to topical

steroid treatment. We have addressed this issue by examin-

ing the local expression of the inducible (p40) subunit of

IL-12 and the functionally important subunit (b2) of the

IL-12R in two models of sinonasal in¯ammation. The ®rst

involved naturally exposed subjects with allergy-associated

(ACS) and nonallergy-associated chronic sinusitis (NCS)

which was compared with normal controls. The second

model involved an intranasal allergen challenge in allergic

rhinitis subjects pretreated with either topical corticoster-

oids or placebo.

Methods

Patient selection Ð chronic sinusitis

Patients who were recruited from the Rhinology clinic at the

Sir Mortimer B. Davis-Jewish General Hospital and all

had a history of chronic hyperplastic sinusitis for more

than 1 year with one or more of the following symptoms:

nasal congestion, facial pain/pressure, postnasal drip and

anosmia. All subjects had evidence on CT scan of sinus

opaci®cation and/more mucosal thickening in at least the

anterior ethmoid sinuses an ostiomeatal complex. Diagnosis

of associated allergy was based on epicutaneous testing to

a panel of common aeroallergens. Patients were excluded

if they had received previous immunotherapy or if they

had received systemic corticosteroids during the month

preceding the study. Antibiotics were withheld for a

period of 4 weeks prior to the study and topical corticoster-

oid sprays were not used for a period of 2 weeks prior to

biopsy. Biopsies from the patients with chronic sinusitis

measured 3±5 mm in size and were obtained endoscopi-

cally from the anterior ethmoid air cells at the time of

surgery. As a control population, nonatopic subjects with

no history of sinus disease or previous surgery were biop-

sied from the middle meatus (under the middle turbinate)

at the time of other endonasal surgery such as septoplasty.

All subjects gave informed consent based on approval from

the Hospital Review Board.

Patient selection Ð allergic rhinitis

Patients were selected from the nasal clinic based on

positive skin tests to ragweed pollen extract. Exclusion

criteria included previous immunotherapy and oral corti-

costeroids in the previous 6 months. Topical corticosteroid

therapy was discontinued for a minimum period of 6 weeks

prior to the initiation of the study. Patients were divided

randomly into two groups. All subjects underwent a 2.5-mm

biopsy from the under surface of the inferior turbinate

outside of the ragweed season at a time when they were

asymptomatic. The subjects then used either a topical

corticosteroid (budesonide 200 mg once daily) or placebo

for a period of 6 weeks. At the end of the 6 weeks all sub-

jects underwent a nasal allergen challenge by spray (1000

PNU) of ragweed pollen extract. At 24 h post challenge,

a second biopsy was taken from the inferior turbinate.

This study met with hospital ethics committee approval

and all subjects gave informed consent.

Tissue preparation

For in situ hybridization, tissue was placed for 2 h in para-

formaldehyde followed by sequential transfers through 15%

sucrose solutions overnight. The tissue was then blocked

and snap frozen in OCT medium using liquid nitrogen-

cooled isopentane. Sections were cut at 10 mm thickness

onto poly L-lysine-coated slides.

In situ hybridization

To detect IL-12 and IL-12R mRNA we employed the tech-

nique of in situ hybridization using a digoxigenin-labelled

IL-12 (p40) and IL-12 (b2) receptors 1321

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1320±1325

cRNA probe [13]. The cDNA probe was constructed as

previously described. In brief, the coding region of the

product in question was ampli®ed by PCR. The PCR

product was subsequently cloned into the PCRII vector

and the sequence con®rmed by automated sequences of

both strands. Digoxigenin-11-UTP-labelled antisense and

sense probes were generated from cDNA transcribed in

the presence of SP6 or T7 polymerases, respectively. The

sections were permeabilized with proteinase K and then

prehybridized with 50% formamide and 2X standard saline

citrate. Following application of the probe, the sections

were hybridized at 428C overnight. Non-speci®c binding

was removed by post-hybridization washing under high

stringency conditions and subsequent treatment with

RNase. The hybridization signal was visualized by incu-

bating the sections overnight with sheep polyclonal

antidigoxigenin antibodies conjugated with alkaline phos-

phatase. Colour development was achieved by adding the

freshly prepared substrate (X-phosphate-5-bromo-4-chloro-

3-indoly phosphate and nitroblue tetrazolium). To ensure

the speci®city of our signal, we performed the ISH tech-

nique using the sense probe, and following pretreatment

of the tissues with RNase.

Quanti®cation

A blinded observer using an eyepiece graticule at 200 ´magni®cation counted sections. At least two sections were

immunostained or hybridized from which six to eight

®elds were counted. Subepithelial expression was presen-

ted as the mean counts of cells expressing mRNA or protein

per high power ®eld (0.202 mm2).

Statistical analysis

To compare the expression of IL-12/IL-12R in ACS,

NCS and controls, ANOVA analysis was employed (Systat

v5.1, SPSS Inc., Chicago, IL, USA). Differences in expres-

sion prior to and after allergen challenge was determined

using a Wilcoxon signed rank test.

Results

Patient demographic data

As presented in Tables 1 and 2, the mean age and sex

distributions for the different patient groups were compar-

able. In the chronic sinusitis group (Table 1) the serum IgE

and eosinophil counts roughly correlated with atopic status.

IL-12 (p40) expression following allergen challenge

In the patient group which was placebo treated prior to

allergen challenge, IL-12 expression (p40) was signi®cantly

decreased following challenge as compared with their

baseline biopsies (P < 0.05; Fig. 1). In the steroid-pretreated

group, this decrease in IL-12 expression (p40) was not

observed. That is, there was no signi®cant difference

between the level of expression from baseline (pre-) to

post-challenge. The delta value (comparing the pre- and

post-challenge differences between placebo and steroid-

treated groups) was signi®cantly different (P< 0.05).

IL-12 receptor (b2) expression following allergen challenge

In placebo-pretreated patients, there was a non-signi®cant

trend towards a decrease in IL-12Rb2 expression following

allergen challenge as compared with baseline. In the steroid-

treated group there was a statistically signi®cant increase

in IL-12R (b2) expression post-challenge as compared with

baseline (P< 0.05, Fig. 2). The delta value between these

two groups was statistically signi®cant.

1322 E. D. Wright et al.

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1320±1325

Allergy-associated Nonallergy-associated

Control chronic sinusitis chronic sinusitis

n 9 8 7

Mean age (years) 37 39 45

Male:Female 7:2 5:3 4:3

Mean serum IgE (IU) 107.3 175.2 102.9

Serum eosinophils (´ 109/L) 0.20 0.55 0.25

Table 1. Demographic data for chronic

sinusitis group. Mean serum IgE and

serum eosinophils roughly correlate

with atopic status

Table 2. Demographic data for allergen challenge group

Steroid Placebo

pretreatment pretreatment

n 9 10

Mean age in years (range) 35.2 (21±56) 38.1 (26±49)

Female:Male 5:4 4:6

IL-12 (p40 subunit) expression in chronic sinusitis

In both allergy-associated (ACS) and nonallergy-associated

chronic sinusitis (NCS) the expression of IL-12 (p40) was

signi®cantly decreased as compared with controls (P< 0.05,

Fig. 3). There was no difference observed between ACS

and NCS groups.

IL-12 receptor (b2) Expression in Chronic Sinusitis

IL-12R (b2) expression was decreased in ACS subjects

as compared with controls (P< 0.05, Fig. 4). IL-12R (b2)

was also decreased as compared with NCS subjects

(P < 0.05, Fig. 4). There was no signi®cant difference

between control and NCS subjects.

IL-12 (p40) and IL-12 (b2) receptors 1323

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1320±1325

40

30

20

10

0

IL-1

2 +v

e ce

lls/h

pf

Pre

Placebo

Post Pre

Steroid

Post

P < 0.05 NS

P < 0.05

Fig. 1. IL-12 (p40) expression in inferior turbinate biopsies

following allergen challenge. There was a signi®cant decrease in

IL-12 (p40) expression following allergen challenge. This decrease

was not observed when patients were pretreated with topical

corticosteroids.

40

30

20

10

0

IL-1

2R +

ve c

ells

/hp

f

Pre

Placebo

Post Pre

Steroid

Post

P < 0.05NS

P < 0.05

Fig. 2. IL-12 Receptor (b2) expression in inferior turbinate

biopsies following allergen challenge. There was no difference in

IL-12R (b2) expression following allergen challenge. There was,

however, a signi®cant increase in receptor expression after steroid

pretreatment.

75

50

25

0

IL-1

2 +

ve c

ells

/hp

f

CTL ACS NCS

P < 0.05

P < 0.05

Fig. 3. IL-12 (p40) expression in ethmoid sinus tissue of patients

with chronic sinusitis. In both allergy-associated and nonallergy

associated chronic sinusitis subjects there is decreased expression

of IL-12 (p40) as compared with control biopsies from the middle

meatus.

30

20

10

0

IL-1

2R (

β 2)

+ve

cells

/hp

f

CTL ACS NCS

P < 0.05 P < 0.05

Fig. 4. IL-12 receptor (b2) expression in ethmoid sinus tissue

of patients with chronic sinusitis. IL-12R (b2) expression was

decreased in ACS subjects as compared with NCS subjects as well

as with control biopsies from the middle meatus. There was no

signi®cant difference between CTL and NCS.

Discussion

Our data demonstrates that in an allergen challenge model

for allergic rhinitis, IL-12 (p40) expression is decreased

following challenge. In patients pretreated with topical

corticosteroids, this decrease was abrogated. The receptor

for IL-12 (b2) followed a similar pattern except there was a

signi®cant increase in its expression in steroid-pretreated

subjects. The allergen challenge model represents an acute

allergic process, suggesting that within 24 h there is a

dynamic downregulation of this TH1-associated cytokine.

This is in contrast with atopic chronic sinusitis where

the eosinophilia is associated with CD4� cellular in®ltrate

and a TH2-type cytokine pro®le including IL-4, IL-5 and

IL-13. Based on our results, it can be suggested that IL-12

may play a role in orchestrating this response. While our

data does not clearly elucidate a mechanism for the action

of IL-12 and its receptor in this role, it is suggestive.

It appears that the acute allergic process can be modi®ed

by topical corticosteroids since pretreatment prevented

the previously seen decrease in IL-12 (p40) expression

after allergen challenge. Further, steroid pretreatment may

also result in an upregulation of the IL-12R (b2), following

allergen challenge. This ®nding is consistent with previous

data in which systemic steroid treatment of steroid-sensitive

asthmatics resulted in an increased expression of IL-12 [8].

These authors concluded that the clinical effects of gluco-

corticoids are at least partially mediated through the modu-

lation of cytokine production, a ®nding that is further

supported by the ®ndings of the current study. The limita-

tion of the current study, however, is that it does not clarify

whether the observed effects of topical steroids on IL-12/

IL-12R are directly or rather indirectly mediated through

other cytokines such as IL-4 or IFNg. These questions

might be effectively answered using in vitro techniques

such as cell culture or a tissue explant model.

In the chronic sinusitis model, there was low expression

of IL-12 (p40) in both ACS and NCS. Interestingly, the

expression of IL-12R (b2) was low only in ACS subjects,

with expression in NCS and controls being similar. The

®nding of decreased expression of IL-12 in ACS subjects,

with their background of chronic atopic in¯ammation, is

not unexpected in view of previous publications detailing

increased expression of TH2-type cytokines such as IL-4,

IL-5, and IL-13 in ACS patients [14]. One might have

expected that there would be increased expression of

IL-12 (p40) in NCS subjects since the in¯ammatory pro-

cess is nonatopic. Based on our own studies and those of

others [14,15], the typical in¯ammatory cell in®ltrate

associated with nonallergy-associated chronic sinusitis is

characterized by eosinophilia and increased expression of

TH1-type cytokines such as IFNg and IL-2. Additionally,

the ®ndings of this study are in contrast with ®ndings in

patients with atopic dermatitis, who had increased expres-

sion of IL-12 in subjects with chronic lesions as compared

with those with acute lesions [16].

The recent literature examining allergic rhinitis has

raised the question of whether in¯ammatory responses are

regulated locally at the site of disease or via a differential

recruitment of cells. A recent paper has examined the local

expression of IgE and sought to determine whether local B

cells switch to and produce IgE or whether these new IgE-

producing cells are recruited from regional tissues [17]. This

novel and exciting avenue of research applies to the current

study. While our data supports a regulatory role for the

IL-12 (b2) receptor, it does not answer the question of

whether the receptor expression is regulated in the sino-

nasal mucosa or whether differential recruitment of in¯am-

matory cells (T cells) is responsible. This question could

be elegantly addressed by employing a tissue explant model.

The suggestion has previously been made that regulation

of T-helper phenotype development in mouse T cells is

regulated by the expression of the IL-12R [18]. The authors

of this study speculated that in the development of TH2

cells, one of the receptor chains was absent or modi®ed,

making the cells incapable of responding to IL-12. The

result of this unresponsiveness is differentiation down the

TH2 pathway. The ®nding in the present study of decreased

expression of IL-12R (b2) in ACS subjects, represents

in vivo support in humans of the notion that atopic

in¯ammation is associated with decreased expression of

the IL-12R. Additionally, the fact that steroid pretreatment

in allergen-challenged subjects resulted in upregulation of

IL-12R expression is further evidence that suppression

of the in¯ammatory response by IL-12 is exerted via

IL-12R (b2).

Another recent study examining expression of the IL-12R

(b2) subunit in developing human T-helper cells demon-

strated that the IL-12R is expressed on human TH1 but

not TH2 clones [19]. In view of this data, the increased

expression of IL-12R in steroid-pretreated patients is

likely due to modi®cation of the T-helper cell pro®le by

the corticosteroids. This is consistent with the fact that

IL-12 is produced primarily by B lymphocytes, monocytes

and dendritic cells and that IL-12R are primarily expressed

on T lymphocytes and activated NK cells.

Of recent note is a paper that described a decrease in

IL-12 production by splenic antigen-presenting cells that

were treated with dexamethasone [20]. These authors con-

cluded that treatment of atopic disease with chronic cortico-

steroids might indirectly exacerbate the course of the

disease by upregulating TH2 cytokine production. Inter-

preted in view of our current data, this conclusion is not

necessarily the case. It is possible that the signi®cant and

primary role of corticosteroids may be via their action on

T cells, and in this speci®c case via the upregulation of

1324 E. D. Wright et al.

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1320±1325

IL-12R on T-helper cells. with increased expression of the

functional IL-12R subunit, the cells would be more sensitive

to any IL-12 present, even if it was present in decreased

amounts.

In conclusion, the data presented in this paper supports

a role, in vivo, for IL-12 and its receptor as a suppresser of

sinonasal allergic in¯ammation. The data also suggests that

control of this suppression may be largely exerted via the

IL-12 (b2) receptor. Finally, the evidence also indicates that

topical corticosteroids may exert their anti-in¯ammatory

effects via upregulation of IL-12R b2.

Acknowledgements

The authors thank Hoffman-LaRoche Research (Nutley, NJ)

for the IL-12Rb2 cDNA, and Genetics Institute (Cambridge,

MA) for the IL-12 (p40) cDNA. Q. H. Is a Research Scholar

of the Fonds de Recherche en Sante du Quebec.

This study was supported by the Medical Research

Council of Canada (MT-13273).

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