The active secretion of a subunit of IL-12 by tissue cells is regulated by Valosin-Containing Protein and intracellular calcium redistribution.

One molecular mechanism for collaboration between innate immune and tissue stromal cells in regulating effector responses is the formation of the innate cytokine IL-12 as a result of the two cell types contributing distinct subunits (p40 and p35) allowing for the localized assembly of the functional IL-12 heterodimer. Dendritic cell activation leads to p40 secretion, but the pathways in stromal cells allowing p35 secretion are unknown. We identify the inhibition of Valosin-Containing Protein (VCP) and increases in intracellular calcium signaling as the key regulators for the secretion of p35 from its homeostatic reservoirs in the endoplasmic reticulum. This p35 secretion, in the absence of co-expression of the p40 subunit, requires active gene expression, is independent of ER stress pathways, and is distinct from passive (cell-death dependent) release processes. Thus, an active sensory apparatus in non-hematopoietic cells contributes to the collaborative control of the trajectory of early immune differentiation.