Allergen-induced activation of mast cells—which triggers the rapid release of histamine-containing granules and the slower synthesis of inflammatory cytokines—is often thought to be an all-or-none process. Not so, say Klemm and colleagues (page 337), who identify two adaptor proteins that are required for cytokine production by mast cells but are dispensable for degranulation.
The adaptor molecules in question—Malt1 and Bcl10—are required for the activation of the transcription factor NF-κB in T and B cells. But a role for these adaptors in mast cells had never been addressed. Klemm et al. now show that mice lacking either Malt1 or Bcl10 failed to develop late-phase anaphylactic responses, which depend on the production of NF-κB–dependent cytokines. By contrast, acute anaphylaxis—which is driven by mast cell degranulation—was normal in the deficient mice.
Whether physiological situations exist in which mast cells degranulate without producing cytokines is unknown. But the discovery of adaptors that uncouple these signaling pathways might provide a way to block the production of mast cell-derived cytokines, which perpetuate inflammatory diseases such as chronic severe asthma, without hindering degranulation.
Although the advantages of leaving degranulation intact might not be obvious, especially to those who sneeze their way through hay fever season, this process has benefits. One benefit is protection against the damaging side effects of endothelin-1, a potentially harmful vasoactive peptide that is produced by endothelial cells in response to stress and is degraded by mast cell proteases.