These studies clearly demonstrate that cytokines in combination have different effects on fibroblast proliferation than they have individually. In accord with our previous reports, they demonstrate that rIL-1 and rTNF, individually, stimulate fibroblast proliferation and that rTNF-7 can stimulate or inhibit fibroblast proliferation. Importantly, they also show that while combinations of rIL-1, rTNF and rIFN-7 inhibit fibroblast proliferation via at least 2 different mechanisms (Fig 1).
Types 1 and 3 collagen are the major collagens in the lung. Thus, studies were undertaken to determine whether rIL-1, rTNF and rIFN-7, alone and in combination, altered the production of these moieties. Under serum-free conditions, rIL-1 (a and p) and rTNF stimulated while rIFN-7 did not consistently alter fibroblast production of types 1 and 3 collagen (Fig 2 and 3 and data not shown). The stimulatory effects of rIL-1 and rTNF were dose-dependent and neutralized by preincubating each cytokine with its respective neutralizing antibody (data not shown). At their peak, a twofold to fourfold increase in production of both collagen moieties was noted (Fig 2 and 3 and data not shown). In the presence of serum, rIL-1 (a and P), rTNF, and rIFN-7 individually inhibited the production of types 1 and 3 collagen (data not shown). Thus, the presence or absence of serum (the state of activation of the target cell) played a significant role in determining the effects of these cytokines on fibroblast collagen production. buy diabetes drugs
Figure 1. Cytokine network regulating fibroblast proliferation. The effects of cytokines individually are illustrated in the top half of the figure. The effects of the cytokines in combination are in the bottom half of the figure. Individually, IL-l-p, IL-l-a (illustrated as a cell associated moiety) and TNF stimulated fibroblast proliferation. IFN-7 could stimulate or inhibit fibroblast proliferation depending on the state of activation of the target cell. Combining IL-1 or IFN-7 with TNF synergistically inhibited fibroblast proliferation.
Figure 2. Representative experiment demonstrating of the effect of rIL-l-a on the production of type I collagen by quiescent fibroblasts. Fibroblasts were incubated in the presence and absence of rIL-l-a as noted. Collagen levels were assessed by RIA. The collagen content of supernatants from rIL-1 stimulated fibroblasts is expressed as a percentage of the levels in supernatants from control cells.
Figure 3. Representative experiment demonstrating of the effect of rTNF on the production of type 1 collagen by quiescent fibroblasts. Fibroblasts were incubated in the presence and absence of rTNF as noted. The collagen levels in the resulting supernatants were assessed by RIA.
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