Molecular Mechanisms in Allergy and Clinical Immunology
IL-11: Insights in asthma from overexpression transgenic modeling,☆☆

https://doi.org/10.1067/mai.2001.118510Get rights and content

Abstract

The evolution of our understanding of IL-11 mirrors, in many ways, the problems that are faced by investigators in the post-genome era and the types of techniques that might need to be used to deal with these issues. IL-11 was discovered as a soluble factor in fibroblast supernatants that stimulated the proliferation of “IL-6–dependent” plasmacytoma cells. It was subsequently demonstrated to be an important stimulator of platelet reconstitution and a pleiotropic regulator of nonrespiratory tissues. In the lung, IL-11 is produced by a variety of structural cells and eosinophils in response to a variety of stimuli, including TGF-β, major basic proteins, and viruses. IL-11 is also detected in exaggerated quantities at sites of virus infection. Its potential effector functions at these sites were defined with constitutive and inducible overexpression transgenic modeling systems which demonstrated that IL-11 causes nodular mononuclear infiltrates, airway remodeling with subepithelial fibrosis, airways obstruction, and airways hyperresponsiveness and can block alveolar development when expressed during development. In accord with these murine findings, IL-11 is selectively expressed in eosinophils and epithelial cells in patients with moderate and severe asthma where expression correlates directly with disease severity and inversely with FEV1. Studies using transgenic mice also demonstrated that IL-11 inhibits antigen-induced tissue inflammation. Thus IL-11 might be an important regulator of inflammatory and remodeling responses in the asthmatic airway. (J Allergy Clin Immunol 2001;108:489-96.)

Section snippets

The Il-11 Cytokine and Receptor System

After the discovery of human IL-11 and the description of murine IL-11 in 1992, subsequent studies provided knowledge of the structure of the genes that encode these moieties and the proteins that they produce. The human and murine IL-11 genes both contain 5 exons and 4 introns, are 80% homologous at the nucleotide level, and have been mapped to chromosome 19 (q13.3-q13.4) and to the centromeric region of chromosome 7, respectively.2, 3 The 5′ flanking region of the human IL-11 gene contains a

Extrapulmonary Effector Functions of Il-11

IL-11 is a pleiotropic cytokine (Fig 1) with hematop-oietic, osseous, and mucosal protective effects that have received significant investigative attention and lesser understood effects on immune cells and other tissues.

. Schematic illustration shows the stimuli that induce IL-11 production, the cells that produce IL-11 in the lung, and the major effector functions of IL-11 in pulmonary and extrapulmonary tissues.

In the hematopoietic system, IL-11 interacts with other early and late growth

Il-11 in the lung

To define the role(s) of IL-11 in pulmonary homeostatic responses, early studies from our laboratory and others used in vitro approaches to determine which lung cells have the ability to produce this cytokine. At baseline, IL-11 mRNA was not detected or was barely detected in normal lung tissue and a variety of primary lung cells and transformed lung cell lines. In contrast, appropriately stimulated fibroblasts, epithelial cells, human airway smooth muscle cells, and eosinophils were noted to

Overexpression transgenic modeling of Il-11

At the conclusion of the experiments noted above, experimentalists were faced with a dilemma that is characteristic of the post-genome era. They knew that the protein product of the gene in question (IL-11) was produced in large quantities by lung cells and was present in exaggerated amounts in secretions from patients with lung disease. However, the effector functions of the protein in the lung were completely undefined. To begin to define the effects of IL-11 in the lung, overexpression

Il-11 in human asthma

The utility of an animal modeling system ultimately depends on the degree to which the paradigms that are operative in the model reflect events in human tissues. As a result of the studies noted above, we hypothesized that IL-11 plays an important role in the pathogenesis of the airway events in human asthma. To begin to test this hypothesis, we collaborated with Minshall et al42 in studies in which in situ hybridization and immunohistochemistry were used to evaluate the expression of IL-11

Effects of Il-11 on airway inflammation and injury

The studies noted above demonstrate that IL-11 induces tissue fibrosis and is found in exaggerated quantities in airway biopsies from patients with asthma. Studies were next undertaken to determine whether this IL-11 was produced as a manifestation of disease pathogenesis and/or a manifestation of airway healing and repair. We reasoned that cytokines that are involved in healing and repair would simultaneously induce tissue fibrosis and the resolution of tissue inflammation (as seen with

Summary

Our knowledge of IL-11 has progressed impressively. We started with a bioactivity and then used traditional cloning and protein expression approaches to characterize the structure of the IL-11 genes and the proteins that they encode. A variety of in vivo and in vitro approaches were subsequently used to investigate the effector profiles of these proteins and their role(s) in biology. Overexpression transgenic modeling was particularly important, because it demonstrated that IL-11 induces an

Acknowledgements

We thank Katherine Bertier for her excellent secretarial and administrative assistance.

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  • Cited by (0)

    Supported by NIH grants HL-56389, HL-61904, and HL-64242 (J. A. Elias).

    ☆☆

    Reprint requests: Jack A. Elias, MD, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Department of Internal Medicine, 333 Cedar Street/105 LCI, New Haven, CT 06520.

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