Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1993 Jul;79(3):479–484.

The release of transforming growth factor-beta following haemorrhage: its role as a mediator of host immunosuppression.

A Ayala 1, D R Meldrum 1, M M Perrin 1, I H Chaudry 1
PMCID: PMC1421983  PMID: 8406575

Abstract

Haemorrhage in the absence of trauma is reported to induce a profound depression in cell-mediated immunity. Recent studies have drawn attention to the cytokine transforming growth factor-beta (TGF-beta) that, while important in wound healing, also has marked immunosuppressive effects. The aim of this study was to determine whether: (1) haemorrhage induces an increase in circulating TGF-beta and if this is associated with the loss of host immunoresponsiveness; and (2) administration of monoclonal antibody (mAb) to TGF-beta following haemorrhage ablates these changes. To determine this, C3H/HeN mice were bled to and maintained at a mean arterial pressure of 35 mmHg for 1 hr. This required removing approximately 50% of the circulating blood volume. Following this period of hypotension, the mice were adequately resuscitated. Blood samples obtained at 24 and 72 hr, but not at 2 hr, following haemorrhage showed a significant elevation in plasma TGF-beta levels when compared to shams. At 24 hr, the increase of TGF-beta in the plasma was associated with decreases in both concanavalin A (Con A)-induced splenocyte proliferation and splenic macrophage antigen presentation. Treating animals with neutralizing antibody (animals received 200 micrograms mAb against bovine TGF-beta 1,2,3/mouse intraarterially) not only reduced the levels of TGF-beta in the blood at 24 hr, but also restored splenocyte functions, such as Con A-induced proliferation, interleukin-2 (IL-2) release, and the capacity of splenic macrophages to present antigen. However, elevated levels of prostaglandin E2 (PGE2) seen in plasma during haemorrhage were only partially depressed by the antibody treatment. These results indicate that the release of TGF-beta contributes to the protracted (> or = 24 hr) suppression of cell-mediated immunity following haemorrhage.

Full text

PDF
479

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham E., Chang Y. H. Cellular and humoral bases of hemorrhage-induced depression of lymphocyte function. Crit Care Med. 1986 Feb;14(2):81–86. doi: 10.1097/00003246-198602000-00001. [DOI] [PubMed] [Google Scholar]
  2. Abraham E., Freitas A. A. Hemorrhage produces abnormalities in lymphocyte function and lymphokine generation. J Immunol. 1989 Feb 1;142(3):899–906. [PubMed] [Google Scholar]
  3. Ayala A., Perrin M. M., Chaudry I. H. Defective macrophage antigen presentation following haemorrhage is associated with the loss of MHC class II (Ia) antigens. Immunology. 1990 May;70(1):33–39. [PMC free article] [PubMed] [Google Scholar]
  4. Ayala A., Perrin M. M., Ertel W., Chaudry I. H. Differential effects of hemorrhage on Kupffer cells: decreased antigen presentation despite increased inflammatory cytokine (IL-1, IL-6 and TNF) release. Cytokine. 1992 Jan;4(1):66–75. doi: 10.1016/1043-4666(92)90039-t. [DOI] [PubMed] [Google Scholar]
  5. Ayala A., Perrin M. M., Meldrum D. R., Ertel W., Chaudry I. H. Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin. Cytokine. 1990 May;2(3):170–174. doi: 10.1016/1043-4666(90)90012-i. [DOI] [PubMed] [Google Scholar]
  6. Ayala A., Perrin M. M., Wagner M. A., Chaudry I. H. Enhanced susceptibility to sepsis after simple hemorrhage. Depression of Fc and C3b receptor-mediated phagocytosis. Arch Surg. 1990 Jan;125(1):70–75. doi: 10.1001/archsurg.1990.01410130076010. [DOI] [PubMed] [Google Scholar]
  7. Ayala A., Perrin M. M., Wang P., Ertel W., Chaudry I. H. Hemorrhage induces enhanced Kupffer cell cytotoxicity while decreasing peritoneal or splenic macrophage capacity. Involvement of cell-associated tumor necrosis factor and reactive nitrogen. J Immunol. 1991 Dec 15;147(12):4147–4154. [PubMed] [Google Scholar]
  8. Bristol L. A., Ruscetti F. W., Brody D. T., Durum S. K. IL-1 alpha induces expression of active transforming growth factor-beta in nonproliferating T cells via a post-transcriptional mechanism. J Immunol. 1990 Dec 15;145(12):4108–4114. [PubMed] [Google Scholar]
  9. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  10. Diaz A., Varga J., Jimenez S. A. Transforming growth factor-beta stimulation of lung fibroblast prostaglandin E2 production. J Biol Chem. 1989 Jul 15;264(20):11554–11557. [PubMed] [Google Scholar]
  11. Ertel W., Morrison M. H., Ayala A., Chaudry I. H. Chloroquine attenuates hemorrhagic shock-induced immunosuppression and decreases susceptibility to sepsis. Arch Surg. 1992 Jan;127(1):70–76. doi: 10.1001/archsurg.1992.01420010084012. [DOI] [PubMed] [Google Scholar]
  12. Ertel W., Morrison M. H., Ayala A., Perrin M. M., Chaudry I. H. Anti-TNF monoclonal antibodies prevent haemorrhage-induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression. Immunology. 1991 Oct;74(2):290–297. [PMC free article] [PubMed] [Google Scholar]
  13. Ertel W., Morrison M. H., Ayala A., Perrin M. M., Chaudry I. H. Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock. Ann Surg. 1991 Mar;213(3):265–271. doi: 10.1097/00000658-199103000-00015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kaye J., Gillis S., Mizel S. B., Shevach E. M., Malek T. R., Dinarello C. A., Lachman L. B., Janeway C. A., Jr Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. J Immunol. 1984 Sep;133(3):1339–1345. [PubMed] [Google Scholar]
  15. Livingston D. H., Malangoni M. A., Sonnenfeld G. Immune enhancement by tumor necrosis factor-alpha improves antibiotic efficacy after hemorrhagic shock. J Trauma. 1989 Jul;29(7):967–971. doi: 10.1097/00005373-198907000-00010. [DOI] [PubMed] [Google Scholar]
  16. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  17. Meldrum D. R., Ayala A., Perrin M. M., Ertel W., Chaudry I. H. Diltiazem restores IL-2, IL-3, IL-6, and IFN-gamma synthesis and decreases host susceptibility to sepsis following hemorrhage. J Surg Res. 1991 Aug;51(2):158–164. doi: 10.1016/0022-4804(91)90088-4. [DOI] [PubMed] [Google Scholar]
  18. Miller-Graziano C. L., Szabo G., Griffey K., Mehta B., Kodys K., Catalano D. Role of elevated monocyte transforming growth factor beta (TGF beta) production in posttrauma immunosuppression. J Clin Immunol. 1991 Mar;11(2):95–102. doi: 10.1007/BF00917745. [DOI] [PubMed] [Google Scholar]
  19. Rana M. W., Ayala A., Dean R. E., Chaudry I. H. Decreased Fc receptor expression on macrophages following simple hemorrhage as observed by scanning immunoelectron microscopy. J Leukoc Biol. 1990 Dec;48(6):512–518. doi: 10.1002/jlb.48.6.512. [DOI] [PubMed] [Google Scholar]
  20. Rappolee D. A., Mark D., Banda M. J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. doi: 10.1126/science.3041594. [DOI] [PubMed] [Google Scholar]
  21. Ruegemer J. J., Ho S. N., Augustine J. A., Schlager J. W., Bell M. P., McKean D. J., Abraham R. T. Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression. J Immunol. 1990 Mar 1;144(5):1767–1776. [PubMed] [Google Scholar]
  22. Stephan R. N., Kupper T. S., Geha A. S., Baue A. E., Chaudry I. H. Hemorrhage without tissue trauma produces immunosuppression and enhances susceptibility to sepsis. Arch Surg. 1987 Jan;122(1):62–68. doi: 10.1001/archsurg.1987.01400130068010. [DOI] [PubMed] [Google Scholar]
  23. Tashjian A. H., Jr, Voelkel E. F., Lazzaro M., Singer F. R., Roberts A. B., Derynck R., Winkler M. E., Levine L. Alpha and beta human transforming growth factors stimulate prostaglandin production and bone resorption in cultured mouse calvaria. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4535–4538. doi: 10.1073/pnas.82.13.4535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wahl S. M., Hunt D. A., Bansal G., McCartney-Francis N., Ellingsworth L., Allen J. B. Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta. J Exp Med. 1988 Oct 1;168(4):1403–1417. doi: 10.1084/jem.168.4.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wahl S. M., McCartney-Francis N., Mergenhagen S. E. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today. 1989 Aug;10(8):258–261. doi: 10.1016/0167-5699(89)90136-9. [DOI] [PubMed] [Google Scholar]
  26. Zhou D., Munster A., Winchurch R. A. Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta. FASEB J. 1991 Aug;5(11):2582–2585. doi: 10.1096/fasebj.5.11.1868982. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES