Surfactant Protein A Activation of Atypical Protein Kinase C ζ in IκB-α-Dependent Anti-Inflammatory Immune Regulation

Abstract

The pulmonary collectin surfactant protein (SP)-A has a pivotal role in anti-inflammatory modulation of lung immunity. The mechanisms underlying SP-A-mediated inhibition of LPS-induced NF-κB activation in vivo and in vitro are only partially understood. We previously demonstrated that SP-A stabilizes IκB-α, the primary regulator of NF-κB, in alveolar macrophages (AM) both constitutively and in the presence of LPS. In this study, we show that in AM and PBMC from IκB-α knockout/IκB-β knockin mice, SP-A fails to inhibit LPS-induced TNF-α production and p65 nuclear translocation, confirming a critical role for IκB-α in SP-A-mediated LPS inhibition. We identify atypical (a) protein kinase C (PKC) ζ as a pivotal upstream regulator of SP-A-mediated IκB-α/NF-κB pathway modulation deduced from blocking experiments and confirmed by using AM from PKCζ−/− mice. SP-A transiently triggers aPKCThr410/403 phosphorylation, aPKC kinase activity, and translocation in primary rat AM. Coimmunoprecipitation experiments reveal that SP-A induces aPKC/p65 binding under constitutive conditions. Together the data indicate that anti-inflammatory macrophage activation via IκB-α by SP-A critically depends on PKCζ activity, and thus attribute a novel, stimulus-specific signaling function to PKCζ in SP-A-modulated pulmonary immune response.