Endogenous anti-inflammatory substances, inter-α-inhibitor and bikunin

There have been new developments in the elucidation of the biological functions of the inter-alpha-inhibitor (I alpha I) family. The anti-proteolytic activity of the I alpha I family originates from bikunin (also known as urinary trypsin inhibitor). Growing evidence indicates that bikunin is not just an anti-proteolytic agent, but can also be considered an anti-inflammatory agent that suppresses lipopolysaccharide (LPS)-induced cytokine synthesis. Bikunin functions to inhibit calcium influx and extracellular signal-regulated kinase (ERK) signaling via LPS receptors and/or as yet unidentified bikunin signaling receptors. By signaling via the LIDS receptor, LIPS increases calcium influx and yields phosphorylated ERK, which activates multiple transcription factors, such as nuclear factor kappa B (NF-kappa B) or early growth response-1 (Egr-1), which in turn promote cytokine expression. Deficits in the signaling cascades caused by free or cell-bound bikunin are predicted to down-regulate cytokine expression, render macrophages/neutrophils more inactive, and impair inflammatory processes. This brief review largely focuses on our current understanding of the apparent functions of bikunin, its ligands, the effector molecules with which it interacts, and its regulation.