1. TNF Induces Interferons When TNF-α is released (primarily by macrophages), it binds to its receptors (TNFR1/TNFR2) and activates the NF-κB signaling pathway . This intracellular signal switches on genes that produce Type I interferons (IFN-α/β) and encourages T cells and NK cells to release IFN-γ (Type II interferon) . 2. Interferons Prime for TNF The process is reciprocal. IFN-γ "primes" the immune environment by upregulating the expression of TNF receptors on cell surfaces . This makes cells significantly more sensitive to any TNF present. Furthermore, IFNs enhance macrophage responsiveness; as a result, when these primed macrophages encounter a secondary trigger like bacterial LPS, they produce far higher quantities of TNF than they would have otherwise . 3. Functional Synergy and Divergence The "Traffic Jam": While they use different "molecular doors"—TNF via NF-κB/MAPK and IFNs via JAK-STAT—they converge on the same downstream targets . Together, they synergistically induce chemokines (like CXCL9, 10, and 11) and adhesion molecules that make blood vessels "sticky," driving intense immune cell recruitment to the site of inflammation . Clinical Distinction: Because these pathways remain mechanistically separate (TNF does not use JAK-STAT), JAK inhibitors block IFN signaling but do not directly stop TNF signaling . This explains why a patient might fail a TNF inhibitor but still respond to a JAK inhibitor, as these drugs enter the inflammatory circuit from different points CAN U CREATE A DIAGRAM EXPLAING THIS FOR PRESENTATION