Corals are marine animals from the class Anthozoa and are widely distributed in tropical and subtropical seawaters. They are considered as an important source of lead compounds for drug discovery. For evaluating the medicinal activities of briarane-type diterpenoids (BrDs) from marine coral Briareum excavatum, the regulation of a group of briarane-type diterpenoids (BrDs) on dendritic cell (DC) function, TPA-induced dermatitis and type 1 diabetes was investigated. The results show that the BrD excavatolide K (BrD2) remarkably suppressed the activation of human DCs, especially the expression of IL-12 p40. This inhibitory effect was mediated apparently by interference with the rictor-mTOR/Akt-mediated signaling network, resulting in persistent-phase activation of NF-kB and Erk1/2 signalings. In addition, the 8,17-epoxide of BrDs was observed to play a crucial role in inhibition of IL-12 p40 expression. Replacement of the C-12 hydroxyl group with longer esters in BrDs gradually decreased this inhibitory activity in human DCs. BrD excavatolide B (BrD1) effectively suppressed the capacity of mouse bone marrow-derived DCs to induce an antigen-specific Th1, response via the inhibition of IL-12 expression. Moreover, excavatolide B prevented the onset of autoreactive T cell-mediated diabetes in NOD/SCID mice. Furthermore, excavatolide B remarkably suppressed TPA-induced vascular permeability and edema in test skin tissues. At the biochemical level, excavatolide B inhibited TPA-induced expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase-9, the key indicators of cutaneous inflammation. This inhibition is apparently mediated by interference with the Akt/NF-kB-mediated signaling network. Together, these studies demonstrate that BrDs from specific marine corals can effectively regulate defined molecular and cellular functions of dendritic cells, suppress TPA-induced dermatitis, and prevent type 1 diabetes in murine models suggesting that BrDs may warrant further investigation as natural immunomodulatory agents or therapeutics.