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 d eposition of extracellular matrix (ECM) around the islets beginning at an early age. This matrix was interspersed with eosinophils, macropha ges, and fibroblasts; T cells were notably absent. As the mice aged, t he exocrine tissue was steadily replaced by ECM and adipose tissue, an d the pancreatic islets were disrupted by ECM deposition and newly for med pancreatic ducts, Most striking was the preferential accumulation of B lymphocytes around the blood vessels close to the islets. Vascula r changes included induction of MadCAM (mucosal addressin cell adhesio n molecule)-1, von Willebrand factor, and intercellular adhesion molec ule-1 on endothelial cells in pancreata of Ins-IL-4 mice. Overall, tis sue-specific expression of IL-4 induced a complex, localized host resp onse that resulted in the excessive generation of ECM and the selectiv e recruitment of inflammatory cells. These findings suggest that IL-4 has a role in (a) the regulation of potentially pathologic fibrotic ev ents associated with chronic inflammatory lesions and (b) the recruitm ent of inflammatory cells in Th2 cell-dependent diseases such as aller gic disorders.