(100d) Modeling Intra- and Inter-Kingdom Signaling Through NF-Kb Pathway in Dendritic Cells

Authors: 
Maiti, S., Texas A&M University
Alaniz, R., Texas A&M Health Science Center
Hahn, J., Rensselaer Polytechnic Institute
Jayaraman, A., Texas A&M University


The human gastro-intestinal (GI) tract is colonized by ~1014 commensal (non-pathogenic) bacteria in close proximity to host epithelial cells [1]. Intra-kingdom (host-host) and inter-kingdom (host-bacteria) communication is integral to proper functioning of GI tract, and helps maintain a delicate balance between a pro-inflammatory response to invading pathogens and tolerance towards commensal bacteria (anti-inflammatory response) [1]. Disruption of this homeostatic balance can lead to indiscriminate phagocytosis of both bacterial and host cells resulting in diseases such as Crohn’s disease and Ulcerative colitis [2]. This study focuses on investigating the inter- and intra-kingdom signaling mechanisms involved in maintaining homeostasis in the GI tract through mathematical modeling and experimental validation.

One of the anti-inflammatory metabolites produced by the commensal bacteria is indole. Indole is generated from dietary tryptophan by the commensal bacteria, using the enzyme tryptophanase A, and is released into the lumen of GI tract [3]. Prior work from our lab [3] has shown that microbiota-derived indole attenuates indicators of inflammation by decreasing production of IL-12 and IL-8 while increasing production of IL-10. More importantly, these studies also showed that indole decreased activation of the pro-inflammatory transcription factor NF-kB in intestinal epithelial cells. Since IL-10 is also shown to decrease NF-kB activation [4], these results suggest that NF-kB signaling is a putative mechanism through which inter-kingdom signaling effects are mediated.

In this work, we have developed a mathematical model that represents the signal transduction pathway in dendritic cells through which each host-derived pro-inflammatory signaling and microbiota-driven anti-inflammatory signaling converge at NF-kB. TNF-α is used as the prototypic pro-inflammatory cytokine while IL-10 and indole are used as the anti-inflammatory input to the model. The integrated model has been developed in MATLAB using ordinary differential equations and unknown parameters have been estimated from experimental data. A regulatory feedback loop for TNF-α has been included to account for the effect of de novo synthesized TNF-α on NF-kB activation. IL-10 and indole signaling models have been integrated into TNF-α model through common nodes among them. Quantitative experimental data on NF-kB activation has been obtained using dendritic cells transduced with a secreted luciferase reporter system.

The model developed in this study is expected to be helpful in determining the points of intersection of pro- and anti-inflammatory responses and the molecular mediators involved in maintaining homeostasis in the human GI tract, which would in turn help in designing therapeutic strategies for inflammatory disorders.

References:

1.         Berg, R.D., The indigenous gastrointestinal microflora. Trends in Microbiology, 1996. 4(11): p. 430-435.

2.         Bouma, G. and W. Strober, The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol, 2003. 3(7): p. 521-533.

3.         Bansal, T., et al., The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proceedings of the National Academy of Sciences, 2010. 107(1): p. 228-233.

4.         Dhingra, S., et al., IL-10 attenuates TNF-α-induced NFκB pathway activation and cardiomyocyte apoptosis. Cardiovascular Research, 2009. 82(1): p. 59-66.