Fig. 6.

Model of differential and interactive roles of PKC isoforms in mast cells. (a) The conventional PKC isoforms α and β along with the novel isoforms ϵ and θ exhibit differential functional roles in mast cells with respect to both antigen-induced FcϵRI cross-linking and LPS stimulation. PKC-α and PKC-θ serve similar functions through promoting IL-6 cytokine secretion following antigen stimulation and this is somewhat counter-regulated by PKC-β and ϵ. The specific role of a PKC isoform also appears to be context-dependent as, for example, PKC-α acts as a negative regulator of IL-6 production in response to LPS/TLR-4 signalling yet PKC-θ positively regulates this cytokine in response to LPS. Unlike the other PKC isoforms, the role that PKC-ϵ plays in mast cell functional responses seems to be restricted to the FcϵRI pathway. (b) The signalling mechanisms whereby ES-62 inhibits mast cell function have not been fully delineated, however, we indicate that ES-62 targets key signals involved in mast cell activation such as PKC-α. Through targeting this isoform, ES-62 may also have an indirect effect on other PKC isoforms such as PKC-ϵ (a negative regulator of BMMC responses) which in turn leads to a further reduction in the secretion of pro-inflammatory cytokines. We hypothesise that ES-62 may also target PKC-θ as this isoform has not only been shown to be crucial for full mast cell activation, but it may share redundant or similar roles to PKC-α. Additionally, the expression levels of PKC-θ appear to regulate those of PKC-α and therefore through targeting this isoform, ES-62 may again be indirectly targeting a network of PKC isoforms that includes, but is not restricted to, PKC-α.