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

Cellular acid-base status has been found to exert selective actions on the effector functions of activated macrophages (m phi). We examined the effect s of extracellular pH (pH(o)) on the production of tumour necrosis factor-a lpha (TNF-alpha) induced by lipopolysaccharide (LPS) in resident alveolar m phi. Cells were obtained by bronchoalveolar lavage of rabbits, activated i n 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-alpha mRNA peaked at similar to 2 h. The peak tr anscript abundance was increased at lower pH(o) values. This finding probab ly reflected pre-transcription/transcription effects of pH, in as much as t he stability of TNF-alpha mRNA induced with phorbol ester was unaffected by the experimental pH(o) values. TNF-alpha secretion by LPS-treated m phi de creased at lower pH(o) values. The TNF-alpha content of m phi -conditioned media decreased progressively with decrements in pH(o). The reduced TNF-alp ha secretion at pH(o) 5.5 was accompanied by an increase in the cytosolic T NF-alpha content (compared with that at pH(o) 7.4), indicating that pH(o) a ltered TNF-alpha secretion due, in part, to the intracellular retention of synthesized cytokine (i.e. a post-translation effect). The data show that p H(o) has multiple effects (pre-transcription/transcription and post-transla tion) on TNF-alpha production induced by LPS in resident alveolar m phi. Th ese results suggest that the role of alveolar m phi in inflammatory respons es is modulated by pH(o), which may be important in tumours/ abscesses and sites of infection where the external milieu is acidic.