Mononuclear cells (MC) are important regulators of the fibrotic response, in part through their elaboration of inflammatory cytokines. It is known that fibroblast proliferation is regulated by a complex cascade of cytokine interactions with the interferons (IFN), interleukin-1 family of proteins (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) playing important roles. Mononuclear cells are also known to elaborate soluble factors that stimulate and inhibit fibroblast collagen production and degradation. However, little has been done to define the interactions of these cytokines that are important in regulating collagen accumulation and to determine the molecular mechanisms of these effects. Thus, we plan: 1. To characterize further the effects of recombinant (r) IFNs (gamma and beta), rTNF, rIL-1 (alpha and beta), rIL-6 and TGF-B on lung fibroblast collagen production. The cytokines will be tested individually and in combination to define cytokine-cytokine synergy. Their effect on types I, III, IV and V collagen synthesis will be assessed and compared to their effects on fibronectin synthesis. 2. To characterize the human gene for the tissue inhibitor of mettalloproteinase (TIMP). The initial and rate limiting step in the degradation of collagen is cleavage by collagenase. Collagenase activity is modulated by inhibitors such as TIMP. We have obtained clones encompassing the 5' portion, which probably includes the promoter region, of the human TIMP gene. The gene needs to be characterized in order to define elements which control expression of the gene, including those responsive to cytokines. 3. To charcterize the effect of IFNs (gamma and beta), rTNF, rIL-1 (alpha and beta) rIL-6 and TGF-B on fibroblast production of collagenase and TIMP. The cytokines will be tested individually and in combination. 4. To characterize the molecular mechanisms of the regulatory effects of cytokines on matrix production. Molecular biology techniques will be used to define whether these regulatory events are acting at the level of transcription, mRNA stability or translation and investigate how these processes are altered.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (SRC (17))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Waxman, A B; Einarsson, O; Seres, T et al. (1998) Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 101:1970-82
Elias, J A; Wu, Y; Zheng, T et al. (1997) Cytokine- and virus-stimulated airway smooth muscle cells produce IL-11 and other IL-6-type cytokines. Am J Physiol 273:L648-55
Elias, J A; Tang, W; Horowitz, M C (1995) Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. Endocrinology 136:489-98
Einarsson, O; Geba, G P; Panuska, J R et al. (1995) Asthma-associated viruses specifically induce lung stromal cells to produce interleukin-11, a mediator of airways hyperreactivity. Chest 107:132S-133S
Redlich, C A; Delisser, H M; Elias, J A (1995) Retinoic acid inhibition of transforming growth factor-beta-induced collagen production by human lung fibroblasts. Am J Respir Cell Mol Biol 12:287-95
Elias, J A; Zheng, T; Whiting, N L et al. (1994) IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11. J Immunol 152:2421-9
Zitnik, R J; Kotloff, R M; Latifpour, J et al. (1994) Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol 152:1419-27
Elias, J A; Zheng, T; Whiting, N L et al. (1994) Cytokine-cytokine synergy and protein kinase C in the regulation of lung fibroblast leukemia inhibitory factor. Am J Physiol 266:L426-35
Elias, J A; Zheng, T; Einarsson, O et al. (1994) Epithelial interleukin-11. Regulation by cytokines, respiratory syncytial virus, and retinoic acid. J Biol Chem 269:22261-8
Zheng, T; Nathanson, M H; Elias, J A (1994) Histamine augments cytokine-stimulated IL-11 production by human lung fibroblasts. J Immunol 153:4742-52

Showing the most recent 10 out of 20 publications