Cytokine Networks in the Regulation of Inflammation and Fibrosis in the Lung: Discussion (Part 3)

In: Pulmonary function

15 Nov 2012

IL-l-a mediates fever, stimulates the acute phase response, and is an important regulator of B lymphocyte, T lymphocyte, granulocyte, endothelial cell, macrophage, and fibroblast function. IL-6 is also an important regulator of T cell function, B cell function, the acute phase response, and fever. Thus, cytokine stimulated fibroblasts do more than proliferate and produce matrix in response to inflammatory cytokines. They must also be thought of as important immune effector cells that produce cytokines that regulate local and systemic inflammatory events.
Our studies demonstrated that fibroblasts incubated with rIL-1 and rTNF in combination contain pro-IL-1-p. IL-l-p is produced as 33 kilodalton prohormone that is the proteolytically processed to a 17.5 kilodalton mature moiety before release from a cell. This mature moiety binds to tissue IL-1 receptors and mediates the biologic effects of IL-l-p. In contrast, pro-IL-l-p does not bind to IL-1 receptors and is felt to be biologically inactive.26 Thus, it is impossible to say with certainty what role the pro-IL-l-p plays in IL-1 plus TNF stimulated fibroblasts. However, it is tempting to speculate that fibroblasts at sites of inflammation are simultaneously exposed to IL-1 and TNF and thus accumulate large amounts of pro-IL-l-p. Disruptions of the fibroblast membrane or fibroblast death and cell lysis could then release this pro-IL-l-p allowing it to be proteolytically activated by locally accumulated proteases. This newly activated IL-l-p can then regulate local or systemic inflammatory events. A scenario of this sort might explain the extreme toxicity that is seen in association with tissue necrosis in most organs. buy antibiotics online
Physicians have been aware of the unique appearance of abscesses and granulomas for centuries. Both are characterized by central collections of inflammatory cells and a peripheral rim of fibroblasts and scar tissue. To date, however, the characteristic geography of these lesions has not been adequately explained. Our studies demonstrate complex cytokine networks by which mononuclear cells regulate fibroblast proliferation and collagen production, and in turn, fibroblasts feed back to regulate local inflammatory events.

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