IL-16 is synthesized as a precursor with an apparent molecular weight of 80 kD. IL-16 precursor is proteolytically cleaved intracellularly by caspase-3, yielding pro-IL-16 and the secreted (mature) portion. Both components of IL-16 are now known to regulate T-cell growth. The IL-16 mature protein forms homotetramers of 56 kD; this tetrameric form is essential for IL-16 direct interaction with and cross linking of its receptor, the CD4 antigen. Secreted IL-16 primes CD4+ T cells for IL-2 and IL-15 responsiveness, with a preferential effect on Th1 cells; therefore, IL-16 participates in Th1 inflammation. There is association between IL-16 and TNF signaling; caspases are activated following ligation of TNFR1, and pro-IL-16 is processed to its active form by caspase-3 in airway epithelial cells from individuals with asthma or from allergen-sensitized mice. Interestingly, IL-16 production (but not secretion) is caspase-3-dependent, and the interaction of serotonin to the serotonin type 2 receptor is required for IL-16 secretion. IL-16 contributes significantly to the pathology of inflammatory bowel disease and methicillin-resistant S. aureus pneumonia, which are characterized by secretion of IL-16 through activation of TNFR1. Also, IL-16 suppresses lymphocyte activation and inhibits HIV-1 replication in acutely infected T cells.