Inhibition of tumour necrosis factor-alpha (TNF-α) release from mast cells by the anti-inflammatory drugs, sodium cromoglycate and nedocromil sodium

Abstract

SUMMARY TNF-α is a cytokine thought to be involved in the pathogenesis of asthma and in several other inflammatory conditions. Given recent evidence that mast cells (MC) are an important source of TNF-α, we investigated the effects of two anti-inflammatory drugs, nedocromil sodium (NED) and sodium cromoglycate (SCG). on rat MC-derived TNF-α. We established that at least 2h pretreatment with NED or SCG followed by washing was required to inhibit TNF-α-dependent cytotoxicity by rat peritoneal MC (PMC). A maximum inhibition of TNF-α occurred after 6h treatment. The inhibitory effect of NED and SCG (10−5 10−3 M) was concentration-dependent (20-37% for NED and 16-37% for SCG). The time-course analysis and the use of cycloheximide, an inhibitor of protein synthesis, provided strong evidence that new protein synthesis by the MC is required for this inhibitory effect. Furthermore, 24h treatment with I mM NED inhibited the levels of mRNA for TNF-α by 59-83%. In addition to the effect on TNF-α-dependent cytotoxicity by MC, 20min pretreatment with 10−4M NED and SCG inhibited antigen-stimulated TNF-α release (6h) by 42% and 48%, respectively. Interestingly, the functionally distinct intestinal mucosal MC (IMMC) is unresponsive to these drugs with regard to histamine secretion. However, as with PMC, 2h pretreatment with NED or SCG inhibited TNF-α-dependent cytotoxicity by IMMC. These effects may be important in the action of these drugs in vivo in the late phase reaction in asthma or other inflammatory conditions.