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Regulation of the proinflammatory effects of Fas ligand (CD95L)

J J Chen1, Y Sun, G J Nabel

  • 1Howard Hughes Medical Institute, University of Michigan Medical Center, Departments of Internal Medicine and Biological Chemistry, 1150 West Medical Center Drive, 4520 Medical Science Research Building I, Ann Arbor, MI 48109-0650, USA.

Science (New York, N.Y.)
|November 30, 1998
PubMed

Insights

Fas ligand (CD95L) typically causes inflammation, but transforms into immune tolerance in specific microenvironments. Transforming growth factor-beta (TGF-beta) inhibits neutrophil activation, preventing tumor rejection and aiding allograft acceptance.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Fas ligand (CD95L) exhibits dual roles: inhibiting T cell function in immune-privileged sites and inducing inflammation elsewhere.
  • Understanding the molecular basis for CD95L's divergent effects is crucial for immune modulation.

Purpose of the Study:

  • To define the molecular mechanisms underlying the differential responses to Fas ligand (CD95L) in various tissue microenvironments.
  • To investigate the role of transforming growth factor-beta (TGF-beta) in modulating CD95L-induced immune responses.

Main Methods:

  • Utilized a stably transfected colon carcinoma cell line (CT26-CD95L) for subcutaneous and intraocular injections.
  • Assessed neutrophil activation and tumor rejection in response to CD95L expression.
  • Investigated the impact of TGF-beta on neutrophil activation and tumor survival.

Main Results:

  • Subcutaneous injection of CT26-CD95L led to tumor rejection mediated by CD95L-activated neutrophils.
  • CT26-CD95L cells survived within the intraocular space due to TGF-beta inhibiting neutrophil activation.
  • Exogenous TGF-beta administration to subcutaneous sites protected tumors from rejection.

Conclusions:

  • The interplay between CD95L and TGF-beta creates a microenvironment that promotes immunologic tolerance.
  • This cytokine-mediated tolerance mechanism may offer strategies for ameliorating allograft rejection.
  • CD95L's function is context-dependent, influenced by local cytokine milieu, particularly TGF-beta.

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