Different secretory pathways offer variable modes of release for cytokines. All cells have ≥ 1 variations on the classic secretory pathways depicted in the top panel, whereby proteins (eg, cytokines) synthesized in the ER and Golgi complex are transported in membrane-bound vesicles, granules, or both to the cell surface for release. Although all cells have constitutive pathways, specialized cell types additionally have regulated (granule-mediated) pathways, and some cells have a variation of this process (piecemeal degranulation) in which membrane-bound vesicles are used to selectively transport cytokines from secretory granules to the cell surface. All of these pathways have multiple transport steps, each requiring sets of trafficking machinery molecules to execute carrier budding, movement, and membrane fusion. The bottom panel shows nonclassical secretory pathways, which involve movement of proteins (eg, cytokines) directly from their point of synthesis in the cytoplasm to the external milieu. Various mechanisms proposed for crossing the plasma membrane, as the single transport step required, include the use of membrane transporters, exosome release, microvesicle shedding, or cell lysis for cytokine release.