Agent-Based Modeling Table 1. List of agent based rules. Agents Macrophages IKK NF-kB IkBa Receptors IL-4 IL-12 Th cells LPS TNF-a Movement restrictions Agent rules Produce 1 unit of IKK every 5 ticks Move towards the direction that has the highest LPS count within 5 + cell radius Bind free LPS molecules with unoccupied receptors Activated by the formed TNF-TNFR complex 70% chance to bind to inactive NF-kB Dissociate from the complex after 10 ticks Stimulates Nf- kB, IkBa is ubiquitinated Deactivated by activated IkBa as a result of the transcriptional activity of NF-kB Degrades after a random of 1 to 799 ticks If activated and translocates to the nucleus, asks the macrophage to produce 1 IkBa every 10 ticks, 1 unit of IL-12 with 80% chance and 1 unit of TNF-a If activated, seek out activated NF-kB within radius of 1 Bind to any activated NF-kB, form a complex and both members of the complex become inactivated TLR4 (LPS receptors) become activated when bind to LPS molecules. If activated, then produce 1 unit of TNF-a every 100 clicks IL-4 and IL-12 receptors receive their respective targets (receptors) In the presence of free IL-12, 3 units of IL-4 are produced by 86% for every 1 to 5 clicks Bind to IL-4 receptors on Th-0 cells or macrophages. On macrophages, the binding rate increases the energetic level of the macrophage by 1 Produced by macrophages and Th-1 cells Bind to IL-12 receptors on Th-0 directing the differentiation towards either Th-1 orTh-2 Th-0 cells count the unit of interleukins on its surface receptors. Once the number of interleukins reaches 25, then differentiate into either Th-1 or Th-2. If more IL-12 molecules are present than IL-4, then become Th-1. Otherwise, it becomes a Th-2 type Frequency of movement: 800 times more frequent than other cellular agents Collides with LPS receptors on the surface of macrophages Activates the receptor while the ‘‘sensitivity value’’ decreases by 1 A successful binding occurs if a random value between 1 and the maximum value of sensitivity (which equals to 5) is less than the current sensitivity Activated endotoxin receptors produce 1 unit of TNF-a If binds to its receptor, then degrade 1 to 2 ticks Start with 600 ticks Binds to TNFR on the surface of macrophages Amplifies intracellular IKK activity If it binds to a receptor, then degrade in 50 clicks or in 200 clicks if there is nearby bound IL-4. Degrades by 1 click naturally Intracellular molecules e.g. NF-kB, IkBa, IKK are confined inside the agents of the plasma membrane. Only activated NF-kB and IkBa can enter the nucleus. Before these agents perform any rule based movement, a check is made whether they are facing the membrane, other molecules or the nucleus. If the destination is inaccessible, then they will face another direction until the next move is achieved. Their positions are further updated as the macrophage moves Extracellular molecules cannot enter the nucleus have similar restrictions with the plasma membrane agents doi:10.1371/journal.pone.0009249.t001 human inflammation that included the pro-inflammatory response (P) consisting of the early increased expression of cytokines and chemokines; the anti-inflammatory response (A) that served as the immunoregulatory arm of the host defense system; and the energetic response (E) that involved the expression of genes that participate in cellular bioenergetic processes. Driven by the premise that intracellular signaling cascades activated inflamma- tion-specific transcriptional responses, a NF-kB dependent phys- icochemical host response model was further proposed in [34]. Such a model captured biological information in the form of kinetic rules and signaling cascades for the onset, resolution and control of the inflammatory process. Further, the immune response could be triggered by the activation of the NF-kB signaling module resulting from an activating signal associated with the binding of extracellular signals (LPS) to appropriate receptors (TLR4) [35]. In this study we have sought to describe the host response to endotoxin via interacting molecules and cells based on an integrated ABM framework as shown in Figure 1. Accordingly, each macrophage possessed a cell membrane comprised of agents arranged in a circle around the center of the cell which constitutes the nucleus. Receptors for LPS, IL-4, and TNF-alpha were embedded in the membrane while the inhibitor protein IkBa, IKK, and NF-kB are located in the cytosol. Prior to any external perturbation, NF-kB is inactive in the cytoplasm forming a complex with its primary inhibitor, IkBa. Upon stimulation, NF-kB translocates to the nucleus activating the transcriptional machinery for the up-regulation of the critical transcriptional events [27–29]. During the recognition process of PLoS ONE | www.plosone.org 3 February 2010 | Volume 5 | Issue 2 | e9249