Human pulmonary macrophages utilize prostaglandins and transforming growth factor β1 to suppress lymphocyte activation

Abstract

The ability to activate peripheral blood lymphocytes (PBLs) in vitro with interleukin-2 (IL-2) is suppressed by the presence of autologous human pulmonary alveolar macrophages (AMs). AMs suppress both IL-2-induced proliferation and the induction of lymphokine-activated killer cell (LAK) activity in a dose-dependent manner (79 +/- 6% suppression of LAK activity at a 0.25:1 AM/PBL ratio). Increasing the IL-2 concentration increased baseline LAK activity but did not prevent AM-mediated suppression. At least two different mechanisms of suppression were observed, one diffusible in nature and the other contact dependent. Indomethacin prevented the component of inhibition that diffused across porous polycarbonate membranes, indicating prostaglandins as the diffusible inhibitor. In contrast, indomethacin had no effect when added alone into conventional AM-PBL cocultures, but a combination of indomethacin and anti-transforming growth factor beta 1 (TGF-beta 1) antibody did prevent inhibition. This result suggests that TGF-beta 1 acts as an additional contact-dependent inhibitor. PBLs that were rendered unresponsive to IL-2 completely recovered their responsiveness within 4 days after removing AMs from the coculture. These features suggest that pulmonary macrophages have multiple mechanisms for locally suppressing IL-2 responses and lymphocyte activation.

Lung Lymphocytes Proliferate Minimally in the Murine Pulmonary Immune Response to Intratracheal Sheep Erythrocytes

“…The lungs contain some elements necessary for T cell proliferation, such as dendritic cells which have been shown to be potent antigen-presenting cells in vitro (2) . Overall, however, the lungs are believed to be a relatively anti-proliferative environment for lymphocytes, due to the effects of surfactant (3) and products of alveolar macrophages (4) and pulmonary epithelial cells (5) . Moreover, the net function of alveolar macrophages, the predominant resident phagocyte, is to down-regulate pulmonary immune responses (6) .…”

Lung lymphocyte elimination by apoptosis in the murine response to intratracheal particulate antigen.

“…Several mechanisms limit development of pulmonary immune responses. Alveolar macrophages, the predominant resident phagocyte, are relatively poor antigen-presenting cells (3,4) that secrete factors inhibiting lymphocyte proliferation (5,6). Although alveolar macrophages can transport particles to mediastinal nodes to initiate immune responses (7), eliminating alveolar macrophages increases pulmonary immune responses (8), suggesting that their net effect is inhibitory.…”

Suppression of T-cell activation by pulmonary alveolar macrophages: dissociation of effects on TcR, IL-2R expression, and proliferation

“…A variety of secreted mediators have been demonstrated to contribute to PAM-mediated inhibition of T-cell proliferation in different in vitro models, and these include leukotrienes [3], prostaglandins [4,5], transforming growth factor-β (TGF-β) [6], interleukin-1 receptor antagonist (IL-1-Ra) [7], and nitric oxide [8]. Immunosuppressive steroid metabolites released via the activity of the enzyme dihydroepiandrosterone sulphatase in PAMs [9] may also play a role in this process.…”