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IL-10 production in vitro,2 but IL-30 treatment neither increases nor reduces IL-10 level in serum in mice (unpublished data).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


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  • 1
    Dibra D, Cutrera J, Xia X, Kallakury B, Mishra L, Li S. Interleukin-30: a novel anti-inflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. Hepatology 2012; 55: 1204-1214.
  • 2
    Stumhofer JS, Tait ED, Quinn IIIWJ, Hosken N, Spudy B, Goenka R, et al. Arole for IL-27p28 as an antagonist of gp130-mediated signaling. Nat Immunol 2010; 11: 1119-1126.
  • 3
    Klein C, Wustefeld T, Assmus U, Roskams T, Rose-John S, Muller M, et al. The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. J Clin Invest 2005; 115: 860-869.
  • 4
    Franckhauser S, Elias I, Rotter Sopasakis V, Ferre T, Nagaev I, Andersson CX, et al. Overexpression of IL-6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 2008; 51: 1306-1316.
  • 5
    van Gameren MM, Willemse PH, Mulder NH, Limburg PC, Groen HJ, Vellenga E, et al. Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. Blood 1994; 84: 1434-1441.

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.