Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a main regulator of antiviral and anti-inflammatory pathways in mammals, which is considered to induce type I interferon (IFN) activation and negatively regulate the activation of the canonical and non-canonical NF-kappaB pathways. Parkin plays a novel role in innate immune signaling by targeting TRAF3 for degradation, and maintaining the balance of innate antiviral immunity. Loss-of-function mutations in genes encoding the signaling protein tumor necrosis factor receptor-associated factor 3 (TRAF3) are commonly found in human B-cell malignancies, especially multiple myeloma and B-cell lymphoma (BCL). B-cell TRAF3 deficiency results in enhanced cell survival, elevated activation receptor signaling, and increased activity of certain transcriptional pathways regulating expression of prosurvival proteins. TNF receptor-associated factor 3 (TRAF3) is a highly versatile regulator of immune response. TRAF3 expression in macrophages could be a novel therapeutic target protein for the treatment of acute pancreatitis.