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(Chest. 2001;120:S3.)
© 2001 American College of Chest Physicians

Transforming Growth Factor-ß1 Secretion From Murine Macrophages Is Released by In Vivo Ingestion of Apoptotic Cells*

Mai-Lan N. Huynh, MD; Valerie A. Fadok, DVM, PhD and Peter M. Henson, PhD

* From the National Jewish Medical and Research Center, Denver, CO.

Correspondence to: Mai-Lan N. Huynh, MD, Fellow, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206

(CHEST 2001; 120:3S)

Ingestion of apoptotic cells in vitro by human macrophages induces the secretion of transforming growth factor (TGF)-ß1, which has been suggested to have an anti-inflammatory effect by suppressing the production of proinflammatory cytokines and chemokines.1 Herein we have addressed the mechanisms of TGF-ß1 production in macrophages from ICR mice in vitro and in vivo using enzyme-linked immunosorbent assay and immunofluorescence. Thioglycollate-elicited peritoneal macrophages had detectable TGF-ß1 upon harvest and continued to produce TGF-ß1 in tissue culture for up to 1 week. In vitro uptake of apoptotic Jurkats, and not fresh Jurkats, by the macrophages increased secretion of TGF-ß1 in 3 to 8 h. An antibody directed toward a specific receptor for phosphatidylserine receptor, which has been shown previously to be involved in apoptotic cell recognition and uptake, also enhanced secretion of TGF-ß1 from the cultured macrophages. In vivo uptake of apoptotic Jurkats following intraperitoneal injection into thioglycollate-stimulated peritonea resulted in an even larger increase in TGF-ß1 in fresh lavage fluid. This was not seen with normal Jurkats and was eliminated if the apoptotic Jurkats were opsonized with IgG antibody. This increased secretion from macrophages persisted following isolation from the peritonea and culture for up to 36 h. The released TGF-ß1 was seen as early as 30 min after injection of apoptotic cells, suggestive of an enhanced secretion as well as synthesis. In the lipopolysaccharide-stimulated lung, a similar enhancement of TGF-ß1 in lavage fluid was found after endotracheal instillation of apoptotic Jurkats compared to fresh Jurkats and opsonized apoptotic Jurkats. Resident cells from lung or peritoneum neither contained nor secreted TGF-ß1, although they did release it at 20 h with culture. However, in vivo injection of apoptotic Jurkats to naive lung and peritoneum increased TGF-ß1 production and release into lavage fluid at 1 to 4 h. It is suggested that apoptotic cells, acting in part through the phosphatidylserine receptor, both induce TGF-ß1 synthesis and also release preformed material from macrophages. The above findings implicate a potentially important role of apoptotic cell recognition and clearance in the development of fibrotic disease processes via induction of TGF-ß1.

Footnotes

Abbreviation: TGF = transforming growth factor

Supported by National Institutes of Health grant HL34303.

References

  1. Fadok, VA, Bratton, DL, Konowal, A, et al (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-ß, PGE2, and PAF. J Clin Invest 101,890-898




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