Effects of extracellular pH on tumour necrosis factor-α production by resident alveolar macrophages

Cellular acid–base status has been found to exert selective actions on the effector functions of activated macrophages (mϕ). We examined the effects of extracellular pH (pH_o) on the production of tumour necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in resident alveolar mϕ. Cells were obtained by bronchoalveolar lavage of rabbits, activated in vitro with LPS, and cultured at pH_o 5.5, 6.5 or 7.4 for up to 18 h. The relative abundance of TNF-α mRNA peaked at ~ 2 h. The peak transcript abundance was increased at lower pH_o values. This finding probably reflected pre-transcription/transcription effects of pH, in as much as the stability of TNF-α mRNA induced with phorbol ester was unaffected by the experimental pH_o values. TNF-α secretion by LPS-treated mϕ decreased at lower pH_o values. The TNF-α content of mϕ-conditioned media decreased progressively with decrements in pH_o. The reduced TNF-α secretion at pH_o 5.5 was accompanied by an increase in the cytosolic TNF-α content (compared with that at pH_o 7.4), indicating that pH_o altered TNF-α secretion due, in part, to the intracellular retention of synthesized cytokine (i.e. a post-translation effect). The data show that pH_o has multiple effects (pre-transcription/transcription and post-translation) on TNF-α production induced by LPS in resident alveolar mϕ. These results suggest that the role of alveolar mϕ in inflammatory responses is modulated by pH_o, which may be important in tumours/abscesses and sites of infection where the external milieu is acidic.