Tissue-specific expression of interleukin-4 induces extracellular matrix accumulation and extravasation of B cells.
We have assessed the consequences of tissue-specific production of IL-4 by generating transgenic mice that express IL-4 under the control of the human insulin promoter in the Langerhans' islets of the pancreas. In these transgenic mice, designated Ins-IL-4 mice, we observed the deposition of extracellular matrix (ECM) around the islets beginning at an early age. This matrix was interspersed with eosinophils, macrophages, and fibroblasts; T cells were notably absent. As the mice aged, the exocrine tissue was steadily replaced by ECM and adipose tissue, and the pancreatic islets were disrupted by ECM deposition and newly formed pancreatic ducts. Most striking was the preferential accumulation of B lymphocytes around the blood vessels close to the islets. Vascular changes included induction of MadCAM (mucosal addressin cell adhesion molecule)-1, von Willebrand factor, and intercellular adhesion molecule-1 on endothelial cells in pancreata of Ins-IL-4 mice. Overall, tissue-specific expression of IL-4 induced a complex, localized host response that resulted in the excessive generation of ECM and the selective recruitment of inflammatory cells. These findings suggest that IL-4 has a role in (a) the regulation of potentially pathologic fibrotic events associated with chronic inflammatory lesions and (b) the recruitment of inflammatory cells in Th2 cell-dependent diseases such as allergic disorders.
Mueller
R
R
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Krahl
T
T
Sarvetnick
N
N
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D015815:Cell Adhesion Molecules; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D007249:Inflammation; D007328:Insulin / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009088:Mucoproteins / Q000032:analysis; D009928:Organ Specificity; D010179:Pancreas / Q000276:immunology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D007328:Insulin; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4