JAK2V617F-dependent vs mutation-independent IL-1β and inflammation in MPNs. Blood levels of numerous cytokines, including strongly inflammatory IL-1β, are elevated in all subtypes of JAK2-, CALR- or MPL-mutated MPNs. Several cytokines over-expressed in MPNs, including IL-1β, are produced by nonmutated cells, and inflammation may precede the acquisition of JAK2/STAT5-activating mutations. For instance, autoimmune disease can cause chronic inflammation and IL-1β production, eventually leading to the acquisition of JAK2 CALR or MPL mutations and MPN. In vitro studies showed that expression of CALR mutants did not induce cytokine production. In contrast, JAKV617F clearly increases the expression of IL-1R1, IL-1β and IP-10. In JAK2V617F-mutated MPNs, JAK2V617F-induced expression of IL-1β and IL-1R1 further stimulates cytokine production and inflammation, by both the mutated and nonmutated cells in the bone marrow. Inflammation and JAK1- and JAK2V617F-dependent IL-1β production are sensitive to most JAK inhibitors. In contrast, JAK inhibitors have no effect on IL-1β action, since IL-1β does not signal via JAK/STAT. However, IL-1β can be inhibited by IL-1β antagonists, neutralizing anti-IL-1β antibodies, and NF-κB inhibitors. Importantly, IFN-α represses IL-1β and stimulates T-lymphocyte subsets that secrete anti-inflammatory IL-4, and IL-9, a prothrombopoiesis and prothrombosis cytokine.