Effect of interleukin‐1β, tumour necrosis factor‐α and interferon‐γ on the induction of cyclo‐oxygenase‐2 in cultured human airway smooth muscle cells
Increased levels of several pro‐inflammatory cytokines including interleukin‐1β (IL‐1β) and
tumour necrosis factor‐α (TNFα) have been found in bronchoalveolar lavage fluid from
symptomatic asthmatic patients. IL‐1β, TNFα and interferon‐γ (IFNγ) are known to stimulate
a number of cells to produce inflammatory mediators such as prostaglandins. Although
airway smooth muscle (ASM) is known to be a rich source of prostaglandins, the regulation
of cyclo‐oxygenase (COX) isoforms and prostanoid production by proinflammatory cytokines …
tumour necrosis factor‐α (TNFα) have been found in bronchoalveolar lavage fluid from
symptomatic asthmatic patients. IL‐1β, TNFα and interferon‐γ (IFNγ) are known to stimulate
a number of cells to produce inflammatory mediators such as prostaglandins. Although
airway smooth muscle (ASM) is known to be a rich source of prostaglandins, the regulation
of cyclo‐oxygenase (COX) isoforms and prostanoid production by proinflammatory cytokines …
- Increased levels of several pro‐inflammatory cytokines including interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNFα) have been found in bronchoalveolar lavage fluid from symptomatic asthmatic patients. IL‐1β, TNFα and interferon‐γ (IFNγ) are known to stimulate a number of cells to produce inflammatory mediators such as prostaglandins. Although airway smooth muscle (ASM) is known to be a rich source of prostaglandins, the regulation of cyclo‐oxygenase (COX) isoforms and prostanoid production by proinflammatory cytokines have not been studied in human airway smooth muscle.
- We studied the effects of IL‐1β, TNFα and IFNγ on the induction of two isoforms of cyclo‐oxygenase and its relation to prostaglandin E2 (PGE2) release and COX activity (reflected by PGE2 synthesis from exogenous arachidonic acid) in human cultured airway smooth muscle cells.
- IL‐1β, but not TNFα or IFNγ, caused a time‐ and concentration‐dependent enhancement in PGE2 and other prostanoid (6‐keto‐PGF1α, PGF2α, thromboxane B2 (TXB2) and PGD2) production, with PGE2 and 6‐keto‐PGF1α as the principal products. This stimulation was accompanied by a corresponding increase in COX activity.
- COX‐2 protein measured by Western blot analysis was not detectable in untreated cells, but was increased in a time‐ and concentration‐dependent manner by IL‐1β, but not TNFα or IFNγ. In contrast, no variation in the expression of COX‐1 protein was observed.
- Pretreatment with the conventional non‐steroidal anti‐inflammatory drugs (NSAIDs), indomethacin and ibuprofen, and the selective COX‐2 inhibitors, NS‐398 and nimesulide, completely blocked IL‐1β‐induced PGE2 release and COX activity. The glucocorticosteroid dexamethasone and protein synthesis inhibitors, cycloheximide and actinomycin D, not only markedly inhibited IL‐1β‐stimulated PGE2 release and COX activity but also suppressed IL‐1β‐induced COX‐2 induction.
- This study demonstrates that human cultured ASM cells release prostanoids in response to IL‐1β stimulation and that the response is mostly mediated by the induction of COX‐2 rather than COX‐1 isoenzyme, implying that airway smooth muscle may be an important source of prostaglandins in human airways and that COX‐2 may play an important role in the regulation of the inflammatory process in asthma.
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