From the Obscure and Mysterious Acute Phase Response to Toll-Like Receptors and the Cytokine Network

The discovery of C-reactive protein (CRP) almost 80 years ago in the blood of patients with various infectious and inflammatory diseases initiated studies on the mysterious biological phenomenon called “the acute phase response” (APR). The complex metabolic alterations accompanying APR include changes in the plasma concentration of the majority of liver-produced proteins – acute phase proteins (APPs). The search for mediators released from the site of injury and able to stimulate hepatocytes led to the discovery of “Leukocytic Endogenous Mediator” (or “Endogenous Pyrogen”), initially identified with interleukin-1. Only in 1987 was the main factor able to induce the majority of symptoms of APR discovered and named interleukin-6 (IL-6). The current paradigm assumes that APR is elicited by numerous proinflammatory cytokines, the principal role being played by the IL-6-family. The last decade has brought about significant progress in understanding the initiation of the acute phase response (recognition of pathogens by Toll-like receptors), interaction of cytokines and their receptors (origin and importance of soluble cytokine receptors, construction of hypercytokines by protein fusion), the mechanism of multi-step signal transduction from the plasma membrane to nuclear transcription factors (including the role of MAP kinases), as well as elucidation of the role of receptor cross-talk in cytokine networks in health and disease. Genomic techniques indicate that hundreds of genes participate in the development of APR. The data presented here emphasize the growing importance of APR for clinical medicine and confirm the close relationship between acute phase response and innate immunity.