Interleukin-6 is the Primary Mediator of Hepatic Acute Phase Response
The cytokine directly responsible for the hepatic acute phase response is interleukin-6 (IL-6). 1
Mechanism of IL-6 in Hepatic Acute Phase Response
- IL-6 binds to IL-6 receptors on hepatocytes, triggering intracellular signaling pathways that directly regulate the transcription of acute phase protein genes 1
- IL-6 is the primary mediator that signals hepatocytes to produce the full spectrum of acute phase proteins seen in inflammatory states 2
- The hepatic acute phase response is characterized by altered production of acute phase proteins by the liver in response to inflammation, which is primarily mediated by IL-6 signaling 1
Comparative Role of Other Cytokines
- While interleukin-1 (IL-1β) and tumor necrosis factor-alpha (TNF-α) can modulate some aspects of the acute phase response, they fail to induce critical acute phase proteins like C-reactive protein and serum amyloid A 2
- IL-1β and TNF-α have only moderate effects on positive acute phase proteins and actually inhibit the synthesis of fibrinogen, albumin, and transferrin 2
- Interleukin-2 (IL-2) has no direct role in stimulating hepatocyte production of acute phase proteins and is primarily involved in T-cell proliferation and immune regulation 1
Sources of IL-6 in Acute Phase Response
- Traditionally, IL-6 was thought to be delivered to the liver either in an endocrine fashion from immune cells at the site of injury or in a paracrine manner by hepatic immune cells within the liver 3
- Recent evidence indicates that hepatocytes themselves can be directly induced to synthesize IL-6 in response to challenges like lipopolysaccharide (LPS) or hepatocyte growth factor (HGF), suggesting an autocrine regulatory mechanism 3
- During inflammatory conditions, there is a shift in IL-6 tissue targets, with repression of monocytic IL-6 receptors and stimulation of hepatocytic IL-6 receptor synthesis 4
Clinical Significance
- Measurement of acute phase proteins, particularly C-reactive protein (CRP), is clinically useful for diagnosing and monitoring inflammatory conditions, with CRP being directly induced by IL-6 signaling in the liver 1
- Understanding IL-6 as the primary mediator of the hepatic acute phase response has led to the development of targeted therapies for inflammatory conditions 1
- Persistent activation of the IL-6 signaling pathway can be detrimental to the liver and might ultimately contribute to the development of liver tumors 5