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Interleukin-1 and tumor necrosis factor synergistically stimulate lung fibroblast interleukin-1 alpha production
1Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia.
Insights
Normal human lung fibroblasts produce thymocyte-stimulating activity when exposed to interleukin-1 (IL-1) and tumor necrosis factor (TNF). Combining IL-1 and TNF synergistically enhances this activity, amplifying IL-1
Area of Science:
- Immunology
- Cell Biology
- Inflammation Research
Background:
- Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are key inflammatory cytokines.
- Fibroblasts play a role in immune responses and tissue inflammation.
- Cell-associated thymocyte-stimulating activity is a measure of immune cell modulation.
Purpose of the Study:
- To investigate the expression of cell-associated thymocyte-stimulating activity by human lung fibroblasts.
- To determine the effects of recombinant interleukin-1 (rIL-1) and recombinant tumor necrosis factor (rTNF) on this activity.
- To explore the synergistic interactions between rIL-1 and rTNF in inducing fibroblast activity.
Main Methods:
- Incubation of normal human lung fibroblasts with rIL-1 (alpha and beta) and rTNF.
- Measurement of cell-associated thymocyte-stimulating activity.
- Dose-response studies and combination experiments with gamma-interferon.
Main Results:
- Both rIL-1 and rTNF individually induced thymocyte-stimulating activity, with rIL-1 being more potent.
- Combined rIL-1 and rTNF treatment resulted in a synergistic, dose-dependent increase in activity.
- The activity was mediated by an IL-1 alpha-like moiety, requiring protein synthesis and peaking at 24 hours.
Conclusions:
- Human lung fibroblasts express inducible thymocyte-stimulating activity.
- IL-1 and TNF synergistically enhance this fibroblast-derived activity, amplifying IL-1-mediated inflammation.
- This mechanism may be crucial for amplifying local inflammatory events.
Abstract:
We determined whether normal human lung fibroblasts expressed cell-associated thymocyte-stimulating activity in response to recombinant interleukin-1 (rIL-1) (alpha and beta) and recombinant tumor necrosis factor (rTNF). Individually, rIL-1 and rTNF induced fibroblast expression of thymocyte-stimulating activity, with rIL-1 being significantly more potent. Importantly, combining rIL-1 and rTNF resulted in a synergistic increase in fibroblast thymocyte-stimulating activity. This synergistic interaction was dose dependent for both cytokines and was not noted when gamma-interferon was combined with rIL-1 or rTNF. In all cases, the thymocyte-stimulating activity was the result of an IL-1 alpha-like moiety whose maximal production required protein synthesis. IL-1 alpha activity could be detected after as little as 4 h, peaked after 24 h, and returned toward normal with longer periods of cytokine-fibroblast incubation. However, cytokine-stimulated fibroblasts that no longer expressed IL-1 alpha activity could be induced to re-express this activity with repeat cytokine challenge. Induction of fibroblast IL-1 alpha by IL-1 and/or TNF may be an important mechanism amplifying IL-1-mediated biologic events at sites of local inflammation.