Cytokines

Cytokines are signaling proteins produced by immune cells — including Mast Cells — that coordinate the broader immune response. Unlike Histamine (which acts in seconds), cytokines operate over hours to days. They’re the slow-burn component of mast cell activation.

Mast Cell-Produced Cytokines

Key cytokines released during and after Degranulation:

IL-1β and IL-6: Pro-inflammatory. Drive systemic symptoms — fatigue, malaise, that “sick feeling,” low-grade fever. IL-6 in particular is associated with the brain fog and cognitive impairment of MCAS, as it crosses the blood-brain barrier and promotes neuroinflammation.

TNF-α: Amplifies local inflammation, recruits other immune cells, promotes tissue damage in chronic activation. Pre-stored in small amounts (released immediately) and synthesized in larger amounts (released over hours).

IL-4 and IL-5: Th2-skewing cytokines. IL-4 promotes IgE production by B cells — which creates more IgE triggers for mast cells. A positive feedback loop. IL-5 recruits eosinophils, another inflammatory cell type.

IL-13: Promotes mucus production and smooth muscle hyperresponsiveness. Major contributor to airway symptoms.

IL-33: An “alarmin” — a danger signal released by damaged epithelial cells that directly activates mast cells. When mast cell activation damages tissue, the tissue releases IL-33, which activates more mast cells. Another self-reinforcing loop.

Why Cytokines Explain the “Sick Day” Feeling

When you have the flu, the malaise, fatigue, achiness, and brain fog are caused by cytokines (IL-1, IL-6, TNF-α) — not by the virus directly. In chronic MCAS, the same cytokines are being produced at lower levels but continuously. The result is a chronic, fluctuating version of that sick feeling — which is often attributed to depression or “just being tired.”