Transgene-induced production of IL-4 alters the development and collagen expression of T helper cell 1-type pulmonary granulomas

Abstract

A number of complex mechanisms regulate the size and cellularity of an Ag-dependent granulomatous reaction and their accompanying cytokine production profiles. In the present study, Th1 (purified protein derivative (PPD)) and Th2 (schistosome egg Ag)-type granulomas were established to examine the role of IL-4 in lesion development and procollagen type III expression. PPD-sensitized mice were transfected via the airway with an adenovirus construct containing an IL-4 cDNA cassette, and the lungs were embolized with sized Ag-coated Sepharose beads. Granuloma development in response to the PPD bead challenge in control mice primarily consisted of mononuclear cells. In contrast, the overexpression of IL-4 in the IL-4 adenovirus-transfected animals demonstrated a significant increase in cellularity, size, procollagen type III expression, and accumulation of eosinophils. Analysis of mRNA and protein within the lung demonstrated significant expression of IL-4 in only the IL-4 adenovirus-transfected animals. The granuloma lesion size was significantly increased in the IL-4 adenovirus-transfected animals on days 2 and 5, reaching an approximate 50% increase compared with the control groups. Furthermore, procollagen type III mRNA expression was increased in the IL-4 adenovirus-transfected, PPD bead-embolized lungs. In contrast, when IL-4 was neutralized during Th2-type schistosome egg Ag bead granulomas, a decrease in procollagen type III was observed. These data indicate that the progression of certain granulomas may be regulated by the production of IL-4, thus altering the cellularity, size, and matrix composition of the inflammatory response.