The leukocytes that come with milk from infected udders are involved in the production of milk cytokines (75). Cytokines are also present in milk from healthy udders, but composition and concentrations change with both clinical and subclinical mastitis (16) depending on time after exposure, pathogen species, and severity of the disease (76). Proinflammatory cytokines as indicators of early inflammation such as TNF-α appear to reach a peak in 1–12 h after exposure followed by a gradual drop (77), whereas other cytokines can reach their maximum levels at up to 7 days or even later (76) depending again also on the pathogen species. In naturally acquired mastitis, milk concentrations of IFN-γ reached up to 20 ng/ml, whereas maximum reported levels of IL-6, TNF-α, IL-1β, IL-8, and TGF-α were about 90 ng/ml, 25 ng/ml, 8 ng/ml, 1 ng/ml, and 0.5 ng/ml, respectively, values that were significantly higher than in milk from healthy udders (76). In comparison, the control milk samples had maximum levels of about only 0–0.15 ng/ml of IFN-γ, TNF-α, IL-1β, IL-8, and TGF-α (
76).
Milk cytokines are crucial for the development of the newborn's organism and its immune system (78). Cytokines have been also considered for therapeutic use, and in that context, it has been demonstrated that orally administered interferons and cytokines can exert both local and systemic effects (79). TGF-β, for example, when synthesized as an inactive precursor, can be activated during intestinal transit by multiple mechanisms, e.g., by a low pH of 1.5 (65). It is therefore probable that milk cytokines are bioactive after ingestion and digestion. Cytokines have very complex biological functions and can interact with each other. Some can induce the production of others, act synergistically to enhance their effects, inhibit the expression of others, or stimulate the expression of receptor antagonists or receptors of others (76). For example, IL-1 induces the production of IL-1 itself, TNF-α, IL-6, IL-8, and IL-12. In the cases of TNF-α and IL-6, IL-1 can act synergistically to enhance their effects (76). This suggests that cytokines in food could make a difference even if present in apparently small amounts. Almost 30 different cytokines with specific features (65) have been already identified in milk raising the question about their biological immunomodulatory significance as well as their risk for human consumption, which has still to be determined.