Potential conflict of interest: Nothing to report.
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, page 2425, December 2012
How to Cite
Mitra, A., Cutrera, J., Mishra, L. and Li, S. (2012), Reply:. Hepatology, 56: 2425. doi: 10.1002/hep.25862
- Issue published online: 4 DEC 2012
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 22 MAY 2012 11:24AM EST
- Manuscript Accepted: 13 MAY 2012
- Manuscript Received: 11 MAY 2012
Based on our findings, it is conclusive that interleukin (IL)-30 reduces inflammation-induced liver injury; however, the exact mechanisms are not clear.1 One possible mechanism as described in Dr. Fujita's letter is that IL-30 inhibits the IL6-gp130-STAT3 pathway because IL-30 binds to gp130 and inhibits IL-6–induced STAT3 activation.2 As indicated by Dr. Fujita, such an explanation may conflict with the fact that the IL6-gp130-STAT3 pathway also protects the liver.3
To solve this paradox, we offer the following explanation. First, IL-30 binding to gp130 and inhibiting IL-6 signaling is only reported in CD4+ T cells in vitro,2 whereas IL-6–mediated liver protection primarily occurs in hepatocytes in vivo.3 Signaling through 2 different types of cells will not antagonistically prevent liver injury. One could argue that IL-30 should bind to gp130 in hepatocytes if binding to T cells, resulting in an antagonistic effect on IL-6 in hepatocytes; however, there is no evidence to support this argument. Further evidence is needed to support the in vitro observation that IL-30 binds to gp130. Second, IL-30 inhibits the IL-6 plus TGFβ-induced IL-10 production in vitro,2 but IL-30 treatment neither increases nor reduces IL-10 level in serum in mice (unpublished data). Finally, the published data indicate that a physiological level of IL-6 may be beneficial to protect from liver injury,3 whereas overexpression of IL-6 may lead to liver inflammation (injury).4
Dr. Fujita also suggests that IL-30 and EBI3 competitively bind to T cell cytokine receptor (TCCR) resulting in inhibition of inflammation. This competitive binding-dependent anti-inflammation is unlikely because IL-30 inhibits IL-12–mediated liver toxicity in both EBI3−/− and TCCR−/− mice.1
In conclusion, IL-6 might act toward hepatoprotection, but the application for protecting liver injury from therapeutics for cancer patients may be prohibited because a higher level of IL-6 in the serum is associated with reduced cancer patients' survival.4 Furthermore, administration of recombinant IL-6 in cancer patients caused toxic effects such as hepatoxicity.5 Contrary to these examples, IL-30 reduces the toxicity of IL-12 (a cancer therapeutic) treatment in mice.1
- 1Interleukin-30: a novel anti-inflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. Hepatology 2012; 55: 1204-1214., , , , , .
- 2Arole for IL-27p28 as an antagonist of gp130-mediated signaling. Nat Immunol 2010; 11: 1119-1126., , , , , , et al.
- 3The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J Clin Invest 2005; 115: 860-869., , , , , , et al.
- 4Overexpression of IL-6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 2008; 51: 1306-1316., , , , , , et al.
- 5Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. Blood 1994; 84: 1434-1441., , , , , , et al.
Abhisek Mitra Ph.D.*, Jeffry Cutrera Ph.D.*, Lopa Mishra M.D., Shulin Li Ph.D.*, * Department of Pediatrics Research, Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.