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During cortisol resistance, a vicious loop occurs that increments all mediators, unbalancing IS, ES, and CNS networks. This IL-1β increase would occur above all when the individual succumbs to stressful events, showing the Sickness Behaviour Symptoms. IL-1β might, through melatonin and vice versa, determine sleep disorders too. The molecular links here outlined could explain how stress plays a role in etiopathogenesis of several diseases through this complex interplay. The molecular links here outlined could explain how stress plays a r