(584t) Modeling the Dynamics of Acute Phase Proteins During the Heat Shock Response

The acute phase response is one of the most important and common responses the human body undergoes in response to trauma, injury, or infection. The production of acute phase proteins as a function of time has been investigated comprehensively at regular body temperature [1-4]. However, since the acute phase response is commonly accompanied by fever [5], modeling the production of acute phase proteins under an elevated body temperature (i.e., heat shock condition) is of utmost importance. In particular, the experimental data presented in Karlsson et al., 1998, [2] indicate that the production of acute phase proteins such as haptoglobin and albumin in HepG2 cells is affected by the temperature even if no IL-6 stimulation is imposed on the hepatocyte cells. Furthermore, the research presented in Kanelakis et al., 2002, has shown a correlation between elevated levels of haptoglobin, and the glucocorticoid receptor (GR) encountered at elevated temperatures [6]. These findings suggest that the expression of acute phase proteins is regulated by elevated body temperature during the heat shock response. Although models for heat shock response exist (see [1, 7] for two existing models), no model has been developed to quantify the dynamics of acute phase proteins during the heat shock response. In order to address this, we extend the heat shock response model presented by Petre et al, 2011 [1], to incorporate the reactions linking the heat shock proteins hsp70 to the expression of two acute phase proteins, i.e., haptoglobin and albumin, which represent the positive and negative acute phase proteins, respectively.   

During the heat shock response, heat shock proteins (hsps) act as “molecular chaperones” to ensure the proper folding of proteins under stress conditions [3]. This response allows the body to better fight off pathogens by raising the body’s own temperature, thus creating unfavorable conditions for the pathogens [3]. Meanwhile, the body’s own proteins are kept in proper working conditions by the hsps. It is reported that hsps are activated upon the elevation of body temperature [1]. The activated hsps then activate glucocorticoid receptors, which then translocate into the nucleus of the hepatocyte [7], interact with C/EBPβ to down-regulate the expression of albumin [8], and interact with both STAT3 and C/EBPβ to up-regulate the expression of hatoglobin [6]. In this work, we added these reactions into the heat shock response model presented by Petre et al, 2011 [1]. The ordinary differential equations for these newly added proteins were developed based upon the mass action and Michaelis–Menten kinetics. The newly added parameters were estimated from the experimental data for albumin and haptoglobin at an elevated body temperature that were presented  in Karlsson et al., 1998 [2]. On the basis of the developed model, sensitivity analysis was conducted to identify the reactions from the heat shock response that play an important role in regulating the synthesis of albumin and haptoglobin. The sensitivity analysis result showed that the most important parameters in the heat shock part of the model were those involving the interaction between hsp and heat shock factors (hsf). Specifically, the most important parameters were those governing the creation and dissolution of the hsp:hsf complex. This may due to the fact that the sequestration of hsf by hsp eventually leads to the suppression of transcription for hsp, which then leads to lowered levels of hsp but increased levels of misfolded proteins (mfp). This effectively functions as a negative feedback loop regulating the long term dynamics of heat shock proteins.

Reference

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