Figure 10

Schematic representative of the in vivo data. Our data suggests that in the mouse inhaled LPS activates TLR4 in the airway to trigger MyD88 dependent increase mRNA production of pro-IL-1α, pro-IL-1β, pro-Caspase 1, pro-caspase 11, ASC and NALP3, but not pro-IL-18 or IPAF. These increases in mRNA levels are likely to be associated with an increase in the corresponding protein levels. The pro-Caspase 1, pro-caspase 11, ASC and NALP3 are then primed ready for a second stimulus (i.e. via ATP-P2X7) and subsequent processing of pro-IL-1β and pro-IL-18. The LPS stimulus causes caspase 1/caspase 11 independent release of IL-1α, IL-1β and IL-18 into the airway lumen (either in the pro or mature form), of which the latter two appear to require IPAF. Pro-forms of the cytokines could be cleaved to the mature forms outside the cell.