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. 1995 Oct;86(2):231–237.

Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations.

N Bilyk 1, P G Holt 1
PMCID: PMC1384000  PMID: 7490123

Abstract

Under steady-state conditions, T-cell activation in the lung is tightly controlled by lymphocytostatic signals from resident pulmonary alveolar macrophages (PAM). The present study focuses upon the mechanism of suppression in the mouse, and how it is bypassed during local inflammatory challenge. Reactive nitrogen intermediates such as nitric oxide (NO) are shown to play a central role in the process as the expression of lymphocytostatic activity by resident murine PAM was abrogated by the NO synthetase inhibitor N-monomethyl-arginine. Overnight pretreatment of resident PAM with granulocyte-macrophage colony-stimulating factor (GM-CSF) abrogated lymphocytostatic activity, with a concomitant small decrease in NO production; this effect was markedly amplified by tumour necrosis factor-alpha (TNF-alpha), but the latter was ineffective alone. The cytokines were inactive if added singly or in combination to fresh PAM:T-cell co-cultures. If GM-CSF plus TNF-alpha exposure of PAM was prolonged beyond 48 hr, both lymphocytostatic and NO-producing capacity were spontaneously re-established. Transforming growth factor-beta (TGF-beta) also inhibited both NO production and lymphocytostatic activity of PAM, but in contrast to GM-CSF and TNF-alpha, TGF-beta was only active if present throughout the PAM:T-cell coculture period. Additionally, monocytes recruited into the lung by a sterile inflammatory stimulus are shown to be initially stimulatory towards T-cell activation, and to progressively develop both T-cell suppressive- and NO synthetic-capacity as they mature into mature PAM in vivo. Thus, during acute lung inflammation, a series of overlapping mechanisms are potentially available to bypass local immunosuppression: secretion of cytokines which are capable of temporarily abrogating the immunosuppressive activity of resident PAM, and the recruitment of permissive monocytes which exhibit potent accessory cell activity, the net result being the creation of a transient 'window' for induction of local T cell-mediated immunity.

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Selected References

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