(316f) Mathematical Modeling for IL6 and IL10 Signal Transduction in Steatosis

Authors: 
Huang, Z. (. - Presenter, Texas A& M University
Moya, C. - Presenter, Texas A&M University
Cheng, P. - Presenter, Texas A& M University
Jayaraman, A. - Presenter, Texas A&M University
Hahn, J. - Presenter, Dept. of Chemical Engineering, Texas A&M University


Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. NAFLD is estimated to affect more than 30 million people in the U.S and is strongly associated with different aspects of the Metabolic Syndrome. The accumulation of fat in hepatocytes (or steatosis) is the initial step that is common to all aspects of the disease, including steatohepatitis [1]. It is becoming evident that pro-inflammatory cytokines such as TNF-α, IL-6 contribute to disease progression [1, 2]. Indeed, circulating levels of IL-6 and its soluble receptor are increased in subjects with NAFLD as compared to normal and steatotic subjects [3]. Furthermore, IL-6 is also the primary mediator of hepatic insulin resistance [4], which further underscores the importance of IL-6 in steatosis. IL-6 signaling in the liver can occur through two pathways - the prototypical Jak-STAT pathway and the Erk-C/EBPβ pathway - to activate the transcription factors STAT3 and C/EBPβ, respectively [5]. Interestingly, the Jak-STAT and Erk-C/EBPβ pathways are utilized differently in steatotic livers. STAT3 activation has been shown to decrease hepatic steatosis in obese mice both by increasing fatty acid oxidation [6] (through PPARα up-regulation) and decreasing fatty acid synthesis (through inhibition of SREBP1c) [7]. On the other hand, recent knockout mice studies have demonstrated that activation of the transcription factor C/EBPβ through the Erk1/2 (MAP kinase) pathway increases steatosis by promoting fatty acid synthesis and lipid accumulation [2]. Together, these studies suggest that the extent of steatosis can be significantly influenced by whether IL-6 signaling occurs through the Jak-STAT and/or Erk-C/EBPβ pathways. Therefore, understanding IL-6 signaling dynamics is important for developing approaches to counter the effects of aberrant IL-6 signaling in steatotic complications.

In addition to IL-6, IL-10 also plays an important role in regulating the activation level of STAT3. As IL-10 signaling utilizes only the Jak-STAT pathway [8], it can lead to STAT3 activation without activating C/EBPβ. When a combination of IL-6 and IL-10 are applied, the IL-10 induced SOCS3 inhibits binding of Jak to the IL-6 receptor but not to the IL-10 receptor; thereby, selectively inhibiting IL-6 signaling [8]. Since no C/EBPβ is activated by IL-10, C/EBPβ activation decreases when IL-6 signaling is inhibited. Therefore, IL-10 can regulate the activation level of STAT3 and C/EBPβ independently. It is clear that while the dynamic behavior of a few individual molecules in the IL-6 pathway is known [9], comprehensive signaling pathway dynamics and interactions for IL-6 and IL-10 signal transduction, as well as their impact on disease progression, are not well understood.

In order to address this issue, this work develops a model for IL-6 and IL-10 signal transduction and then investigates the effect that stimulation with these cytokines has on the activity of STAT3 and C/EBPβ. In an initial step, a previously developed model for IL-6 signaling by Singh et al., 2006 [9], is updated as some of the model parameters are re-estimated based upon newly developed experimental data for the Jak-STAT pathway. Furthermore, the Erk-C/EBPβ pathway is extended in the model to also include the dynamics of the activated transcription factor C/EBPβ in the nucleus. Since IL-10 signals through the Jak-STAT but not the Erk-C/EBPβ pathway, a model for its signal transduction was developed which includes interactions between IL-6 and IL-10 signaling as both mechanisms share signal transduction though the Jak-STAT pathway. Based upon the developed models, detailed simulation studies were conducted and the ratio of the activity of Jak-STAT and Erk-C/EBPβ was investigated for different stimulation levels of IL-6 and IL-10. The results are thoroughly analyzed and the conclusions form the basis for the future design of in vitro and in vivo experiments to test the hypothesis that the relative level of STAT3 and C/EBPβ are an important determinant of steatosis.

References

[1] Lalor PF, Faint J, Aarbodem Y, Hubscher SG, Adams DH. The role of cytokines and chemokines in the development of steatohepatitis. Semin Liver Dis. 2007; 27:173-193.

[2] Rahman SM, Schroeder-Gloeckler JM, Janssen RC, Jiang H, Qadri I, Maclean KN, Friedman JE. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatoclogy. 2007; 45:1108-1117.

[3] Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, Ohata K, Nagaoka S, Matsumoto T, Takii Y, Kusumoto K, Nakamura M, Komori A, Yano K, Yatsuhashi H, Eguchi K, Ishibashi H. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int. 2006; 26:39-45.

[4] Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol. 2001; 96:2957-2961.

[5] Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998; 334(Pt 2): 297-314.

[6] Hong F, Radaeva S, Pan HN, Tian Z, Veech R, Gao B. Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology. 2004; 40:933-941.

[7] Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, Hashimoto N, Kido Y, Mori T, Sakaue H, Teshigawara K, Jin S, Iguchi H, Hiramatsu R, LeRoith D, Takeda K, Akira S, Kasuga M. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Medicine. 2004; 10:168-174.

[8] Murray PJ. The JAK-STAT signaling pathway: Input and output integration. J Immunol. 2007; 178:2623-2629.

[9] Singh A, Jayaraman A, Hahn J. Modeling regulatory mechanisms in IL-6 signal transduction in hepatocytes. Biotechnol. Bioeng. 2006; 95(5):850?862.

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