Role of transforming growth factor-beta(1) in down-regulating TNF production by alveolar macrophages during asbestos-induced pulmonary fibrosis

Our plain-English summary of Role of transforming growth factor-beta(1) in down-regulating TNF production by alveolar macrophages during asbestos-induced pulmonary fibrosis, by I. Lemaire, S. Ouellet (Mediators of Inflammation, 1996).

The study

• Authors: I. Lemaire, S. Ouellet
• Journal: Mediators of Inflammation
• Published: 1996;5(1):37-42
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Activation of alveolar macrophages (AM) for tumour necrosis factor production is suppressed initially during the inflammatory response to fibrogenic dusts. We investigated the mechanisms involved in TNF suppression, notably the role of other AM-derived mediators including prostaglandin E(2) (PGE(2)), transforming growth factor-beta(1) (TGF-beta(1)), and interleukin 6 (IL-6). The action of PGE(2) and TGF-beta(1), on AM was different. At physiologically relevant doses (25-300 pg/ml), PGE(2) did not cause significant inhibition of Hpopolysaccharide (Lps)-induced TNF release by AM in vitro but stimulated IL-6 (up to six fold), an inhibitor of AM-derived TNT. In contrast, TGF-beta(1) (0.5-50 ng/ml) inhibited both LPS-induced TNT and IL-6 release by 50% but had no effect on PGE(2) production by AM. To determine the respective contribution of these different inhibitors in TNF suppression, AM from rats exposed to fibrogenic asbestos for weeks were treated with neutralizing antibody against TGF-beta(1) or indomethacin, an inhibitor of PGE(2) synthesis. Treatment of rat AM with anti-TGF-beta(1) but not indomethacin, abrogated the observed TNT suppression. These results suggest that an autocrine, TGF-beta(1)-dependent mechanism is involved in the down-regulation of TNF production by rat AM from animals with lung fibrosis.

In plain English

This laboratory study used rats and rat lung cells. The authors had earlier reported that, after asbestos exposure, rat lung macrophages stimulated with the bacterial substance LPS showed changes in TNF (an inflammatory signal) production in both directions, starting with a 50% suppression, which this study examined. In normal rat macrophages, PGE2 reduced LPS-induced TNF only at concentrations far above the 805 pg/ml these stimulated cells made. At 25 to 300 pg/ml, it raised spontaneous release of IL-6, a TNF inhibitor, up to six-fold, and LPS-stimulated IL-6 release two- to five-fold. TGF-beta1 cut LPS-induced TNF and IL-6 release by up to 50%, at 2.5 to 5 ng/ml. Rats then received a single dose of UICC chrysotile B asbestos (5 mg) or saline into the windpipe. Three weeks later, their macrophages released more TGF-beta1 than those of saline-treated rats (1.2 versus 0.16 ng/ml). An antibody blocking TGF-beta1 removed the 50% TNF suppression; indomethacin, which blocks PGE2 production, and control turkey serum did not. The authors concluded that the macrophages' own TGF-beta1 appears to suppress their TNF production in rats with lung fibrosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment combined with in vitro (cell culture) experiments on rat alveolar macrophages. It followed up the authors' earlier report of an initial 50% suppression of LPS-stimulated TNF production after asbestos exposure, within changes in both directions.
• Who was studied: Male Wistar rats (225-250 g) from Charles River Canada. Two groups of seven rats each received saline (control) or asbestos. Alveolar macrophages from normal rats were used for the in vitro experiments. Figure 3 and Table 2 report five animals per group.
• Exposure: A single intratracheal injection of UICC Canadian chrysotile B asbestos (5 mg) or saline, with the rats examined 3 weeks later. In vitro, macrophages were treated with LPS, PGE2, TGF-beta1, anti-TGF-beta1 antibody, turkey serum or indomethacin.
• Main results:
  • In macrophages from normal rats, PGE2 inhibited LPS-induced TNF release only at concentrations much higher than the PGE2 levels produced by LPS-activated macrophages (805 pg/ml).
  • In macrophages from normal rats, PGE2 at 25-300 pg/ml stimulated spontaneous IL-6 release (baseline 7 U/ml), by up to six-fold (46 U/ml) at 300 pg/ml.
  • In macrophages from normal rats, PGE2 increased LPS-stimulated IL-6 release (75 U/ml) a further two- to five-fold.
  • In macrophages from normal rats, TGF-beta1 at 0.5 to 50 ng/ml significantly inhibited LPS-induced TNF and IL-6 release. Maximal inhibition (50%) was obtained with 2.5 to 5 ng/ml.
  • In macrophages from normal rats, TGF-beta1 inhibited LPS-induced PGE2 production by 54%. Table 1 shows 805.2 pg/ml with LPS alone and 378 pg/ml with LPS plus TGF-beta1.
  • Asbestos-treated rats had more alveolar macrophages than saline-treated rats (11 million versus 19 million, saline versus asbestos).
  • In macrophages from asbestos-exposed rats, treatment with anti-TGF-beta1 antibody, but not turkey serum or indomethacin, abrogated the 50% suppression of TNF seen 3 weeks after exposure.
  • Macrophage culture media contained 1.2 ng/ml TGF-beta1 for asbestos-exposed rats, compared with 0.16 ng/ml for saline-treated rats (Table 2). The authors state this level is sufficient to inhibit TNF release.
• The authors' conclusion: The authors concluded that TNF production by alveolar macrophages from rats with asbestos-induced lung fibrosis appears to be suppressed in an autocrine way (by the macrophages' own products) through a TGF-beta1-dependent mechanism that does not depend on PGE2.
• Limitations the authors state:
  • The authors state that a contribution from other inhibitors, notably IL-6 and IL-10, cannot be completely ruled out.
  • The authors state that the molecular basis of how TGF-beta1 inhibits TNF production by rat alveolar macrophages is unknown.

Topics

Medical terms in this study, explained in our Lexicon: Transforming Growth Factor-beta (TGF-β), Alveolar Macrophage, Pulmonary Fibrosis, Necrosis, Fibrogenic, Fibrosis.

Related studies

• Alveolar macrophage cytokine and growth factor production in a rat model of crocidolite-induced pulmonary inflammation and fibrosis — K.E. Driscoll, J.K. Maurer, et al. (1995)
• Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats — T.D. Perdue, A.R. Brody (1994)
• Association of transforming growth factor beta1 gene polymorphisms and asbestos-induced fibrosis and tumors — S. Helmig, A. Belwe, et al. (2009)
• Bidirectional modulation of TNF-alpha production by alveolar macrophages in asbestos-induced pulmonary fibrosis — S. Ouellet, H. Yang, et al. (1993)
• Alveolar macrophage stimulation of lung fibroblast growth in asbestos-induced pulmonary fibrosis — I. Lemaire, H. Beaudoin, et al. (1986)
• Relative release of interleukin-1 beta and interleukin-1 receptor antagonist by alveolar macrophages. A study in asbestos-induced lung disease, sarcoidosis, and idiopathic pulmonary fibrosis — J.N. Kline, D.A. Schwartz, et al. (1993)

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