BIOLOGY OF AIRWAY INFLAMMATION
Interleukins involved in the pathogenesis
of chronic airway inflammation
J.A. Lasky (I) and A.R. Brody c2) (*)
(I) Section of ul P monary Diseases, Critical Care and Environmental Medicine,
Department of Medicine, and
(2’ Department of Pathology and Environmental Health Sciences,
Tulane University Medical Center, New Orleans, LA (USA)
39
Introduction
Chronic airway inflammation may arise from a
variety of causes including asthma, smoking-asso-
ciated chronic bronchitis, recurrent aspiration,
chronic infection related to bronchiectasis, cystic
fibrosis and granulomatous processes, such as sar-
coidosis. We will focus our attention on the role of
interleukins in asthma, though many of the causes of
airway inflammation listed above share some com-
mon histopathologic features and pathobiology.
At last count, the interleukins consist of 16 extra-
cellular signalling peptides secreted by lymphocytes
and other cell types. They have chemoattractant,
mitogenic, developmental, activating and survival-
enhancing effects on inflammatory and other cells.
Hence, it is logical to consider their role in the path-
ogenesis of chronic airway inflammation. Since the
majority of recent interleukin-related work in
asthma is based on interleukins 1-6, 8 and 10-13, we
will focus our attention on these.
Interleukins are postulated to cause or abrogate
distinct airway pathologic features. Specifically, the
recruitment of inflammatory cells into the airway
wall, the activation of airway cells within the walls
and lumens, and the development of airway wall
remodeling. An individual interleukin could play a
role in more than one of these processes. For exam-
ple, the chemoattractant and activation effects of
interleukin (IL)-5 on eosinophils are well known
and the chemoattractant and mesenchymal cell mito-
genie effects of ILlp have been documented. In
addition, some of the interleukin activities may be
indirect through induction of other interleukins or
cytokines. Also, different interleukins may have
opposing effects on each of these processes. In
Received December 10, 1996.
murine, and now human studies, T helper lympho-
cytes have been categorized into 2 functional sub-
sets, namely Thl and Th2 (Anderson and Coyle,
1994; Hashimoto et al., 1993). The Thl cells are
primarily involved in cell-mediated immunity and
synthesize IL2 and interferon gamma, whereas the
Th2 lymphocytes are responsible for hypersensitiv-
ity reactions and synthesize IL4, IL5 and ILlO.
Thus, investigators are faced with an ever-
increasing complex of molecules known as the inter-
leukins. We cannot possibly cover all of the biologi-
cal activities of each of these, so in this space we
will concentrate on those activities that could be
playing a role in airway inflammation. It is helpful
to recognize that interleukins have been shown to
regulate each others’ expression in the lung. For
example, IL1 is an important inducer of lL6 mRNA
production, and IL6 in turn synergistically enhances
IL 1 -induced thymocyte proliferation (Akira et al.,
1990). IL1 also induces IL8 and its own secretion
(Dinarello, 1984). Moreover, the activity of one
interleukin may be dependent upon augmentation or
coactivation with another. An illustration of such an
effect is that IL6 appears to be required in order for
IL4 to stimulate IgE synthesis (Vercelli et al., 1988).
In yet another example, CD4+ house-dust-mite-spe-
cific T-cell clones from atopic patients were studied
in vitro and found to have IL2-mediated induction of
IL5 mRNA and peptide production (Mori ei aI.,
1995). In this latter example, IL5 production, desig-
nated as a Th-2-type response, appears to be regu-
lated by a Thl-type interleukin, IL2.
Though much of the literature reviewed herein is
based on animal models of airway inflammation,
there is considerable literature documenting
increased expression of ILl, IL2, lL4, IL5, lL6, IL8
(*) Corresponding author: Arnold R. Brady, Ph. D., Department of Pathology, Tulane University Medical Center, 1430 Tulane Ave-
nue, New Orleans, LA 70112 (USA).

40 68th FORUM IN IMMUNOLOGY
and IL13 in the bronchoalveolar lavage (BAL) fluid
and endobronchial biopsies of humans diagnosed
with asthma (Robinson et al., 1992 ; Bentley et al.,
1996; Zangrilli et al., 1995; Krishnaswamy et al.,
1993). IL8 is also elevated in the sputum of subjects
with COPD (Keatings et al., 1996).
Investigations have been conducted to determine
the cell source(s) of increased interleukin production
in asthmatics. For example, recent combined immu-
nohistochemical and in situ hybridization (ISH)
techniques have revealed that greater than 70% of
cells expressing IL4 or IL5 in bronchial lavage or
bronchial biopsies from asthmatics are CD3+ cells,
and that eosinophils and mast cells also express
messages for these interleukins (Kay et al., 1995).
Immunostaining of bronchial biopsies from asthmat-
ics demonstrate staining in only eosinophils and
mast cells, though this may be due to the fact that T
cells have a limited ability to store cytokines (Brad-
ding et al., 1994). T-cell cytokine profiles have even
recently been evaluated using flow cytometry, and
somewhat surprisingly showed that only about 2%
of T cells recovered from BAL fluid in asthmatics
generate IL4 (Krug et al., 1996).
BAL specimens from non-atopic symptomatic
patients have also been reported to have appre-
ciable levels of ILlp, IL5 and IL6, as detected by
PCR, when compared with non-allergic healthy
control subjects (Marini et al., 1992a). Though all
of the non-atopic patients showed increased ILlp
expression, only half showed increased IL5
expression, despite an increase in eosinophil num-
ber in all non-atopic asthma subjects. Levels of
IL1 p. IL2 and IL6 are increased in the lavage fluid
of symptomatic asthma patients, as compared with
asymptomatic patients with asthma (Broide et al.,
1992). However, lavage specimens were obtained,
in this particular study, from symptomatic patients
undergoing bronchoscopy for diagnostic or thera-
peutic purposes. Since bronchoscopy is not indi-
cated to diagnose or treat asthma, there is some
question as to whether other concomitant pulmo-
nary processes could have contributed to the dif-
ferences seen between the two groups of asthma
patients.
While it is clear that interleukins are produced by
cells from asthmatic and bronchitic airways, the
roles these molecules play in the inflammatory pro-
cess remain unknown. It is hoped that transgenic
and gene knockout models may aid in unraveling the
cytokine web and clarify which cytokines are play-
ing major roles in the pathobiology of airway
inflammation. Investigations into the mechanisms of
airway inflammation have been conducted using IL4
and IL5 knockout mice and in IL6 and IL11 trans-
genie mice. These studies and the use of other ani-
mal models are addressed below under the respec-
tive headings.
IL1
ILlp can induce or amplify airway inflammatory
reactions in several ways, such as through promo-
tion of adhesion molecule expression, inducement of
other interleukins (IL2, IL6, IL8) and cytokines, or
by coactivation of T lymphocytes with IL6 (Akira et
al., 1990; Marini et al., 1992a). ILlp protein is
increased, and macrophages appear to be the pre-
dominant cell type expressing ILlp mRNA in the
BAL of asthmatics (Borish et al., 1992). Since other
lung ceils, such as endothelial cells, epithelial cells,
lymphocytes and fibroblasts express ILlp mRNA,
and since alveolar macrophages have a reduced
capacity to synthesize ILlp in vitro compared with
blood monocytes, the major source of BALF IL10
in asthmatics remains uncertain (Schmidt et al.,
1991). An increase in ILlp immunoreactivity has
also been observed in endobronchial biopsy speci-
mens from subjects with TDI-induced asthma com-
pared with controls (Maestrelli et al., 1995).
ILlp has been shown to play a role in the induc-
tion of the late asthmatic reaction in an Ascaris-sen-
sitized guinea pig model (Okada et al., 1995).
Immunohistochemistry was used to confirm that
IL1 p expression is increased following antigen chal-
lenge, and IL1 receptor antagonist peptides were
used to inhibit eosinophil activation and reduce air-
way hyperreactivity through a proposed PAF-depen-
dent pathway.
Neutralization of IL1 reduces LPS-induced lung
neutrophil accumulation (Ulrich et al., 1991). The
reduced neutrophil accumulation is not unexpected,
because IL1 is a potent inducer of the neutrophil
chemoattractant IL8. In this same line of investiga-
tion, rat monoclonal antibodies against the IL1 type-
1 receptor have been shown to diminish neutrophil
accumulation, granuloma formation and hydroxy-
proline content in mouse lung exposed to heat-killed
bacillus Calmette-Guerin (Denis, 1994). Intratra-
cheal recombinant IL 1 p administration to ovalbu-
mm-sensitized rats results in an increase in the num-
ber of BAL neutrophils at 6 and 18-24 h following
administration, but there is no difference between
sensitized and nonsensitized animals in this model
(Tsukagoshi et al., 1994). IL1 administration also
resulted in an increase in lung resistance in response
to bradykinin, but not acetycholine. Since there was
a strong correlation between neutrophil number and
bradykinin-induced bronchoconstrictor response,
these authors have proposed that IL1 may indirectly
contribute to bronchoconstriction in asthma through
neutrophil-mediated effects on neurogenic mecha-
nisms of bronchoconstriction.
A naturally occurring IL1 receptor antagonist
(IRAP) has been studied in vitro in regard to its
effects on IgE and IL1 p synthesis by peripheral
blood mononuclear cells recovered from asthmatic