Interleukin-6 is the Primary Cytokine Responsible for Hepatic Acute Phase Response
Interleukin-6 (IL-6) is the cytokine directly responsible for the hepatic acute phase response, making option (c) interleukin-6 the correct answer. 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
- 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 to hepatocytes 1
- IL-6 stimulates the synthesis of the full spectrum of acute phase proteins seen in inflammatory states in humans, including C-reactive protein, serum amyloid A, fibrinogen, alpha 1-antitrypsin, alpha 1-antichymotrypsin and haptoglobin, while decreasing albumin, transferrin and fibronectin 2
Comparative Role of Other Cytokines
- Interleukin-1 (IL-1β) and tumor necrosis factor-alpha (TNF-α) have moderate effects on some acute phase proteins but fail to induce critical acute phase proteins like serum amyloid A and C-reactive protein 2
- Interleukin-2 (IL-2) is primarily involved in T-cell proliferation and immune regulation rather than the hepatic acute phase response, with no direct role in stimulating hepatocyte production of acute phase proteins 1
- While earlier research suggested IL-1β, TNF-α, and IL-6 might all be involved in the acute phase response 3, more recent and comprehensive evidence confirms that IL-6 is the major regulator of this process 1, 4, 2
Unique Aspects of IL-6 Signaling in Hepatocytes
- IL-6 receptor expression is stimulated by both IL-1 and IL-6 in cultured human primary hepatocytes, unlike in monocytes where these cytokines downregulate IL-6 receptor expression 5
- Hepatocytes can directly synthesize IL-6 in response to stimuli like lipopolysaccharide (LPS) and hepatocyte growth factor (HGF), suggesting an autocrine regulation mechanism in addition to the traditional endocrine/paracrine model 6
- This autocrine signaling pathway reveals that the hepatic acute phase response can be self-regulated by hepatocytes themselves, not solely dependent on immune cell-derived IL-6 6
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
- In conditions like severe alcoholic hepatitis, the IL-6-mediated acute phase response contributes significantly to the disease pathophysiology 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, 4