Lymphokine/monokine inhibition of fibroblast proliferation and collagen production: role in progressive systemic sclerosis (PSS)

Abstract

A normal fibrotic response to inflammatory stimuli appears to be dependent on the balanced production of a number of stimulatory and inhibitory fibroblast-regulatory mediators by activated mononuclear cells (MNL). To investigate whether altered mediator production contributes to the fibrosis observed in progressive systemic sclerosis (PSS), we stimulated human peripheral blood MNL with concanavalin A (Con A) and lipopolysaccharide (LPS) to produce macromolecular mediators that inhibit the proliferation and the collagen production of cultured normal human fibroblasts. The two Con A-induced mediators were lymphokines (LK) as they were exclusively produced by activated T cells and they coeluted from a Sephacryl S-200 column with a Mr of 50,000. In contrast, the two LPS-induced mediators were monokines (MK) as they were exclusively produced by activated monocytes, and they coeluted in the Mr 20,000 range. Each pair of inhibitory LK and MK may also be distinct as inhibition of collagen production still occurred in proliferatively quiescent cultures. A quantitative comparison of the levels of fibroblast-inhibitory LK/MK produced by normal volunteers and long-term PSS patients revealed that although PSS MNL produced normal levels of both collagen production inhibitory mediators, they were aberrant producers of both proliferation inhibitory mediators, being hypo-producers (-49%) of the LK and hyper-producers (+196%) of the MK. These results suggest that reduced production of proliferation inhibitory LK may allow stimulatory mediators to induce the unrestricted fibroblast proliferation observed in early active PSS, which then may be stabilized in long-term PSS by the increased production of proliferation inhibitory MK.