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Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-\u03baB signaling pathway with the inflammatory gene regulatory responses because NF-\u03baB has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets) to construct the NF-\u03baB signaling pathway and reverse engineering (Network Components Analysis) to build a gene regulatory network (GRN). Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-\u03b1, IL-1, IL-6, CXCL1, CXCL2 and CCL3) is concordant with the NF-\u03baB activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-\u03baB signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-\u03baB regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2105-11-308","type":"journal-article","created":{"date-parts":[[2010,6,22]],"date-time":"2010-06-22T18:16:48Z","timestamp":1277230608000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-\u03baB signaling-induced gene expression responses in inflammation"],"prefix":"10.1186","volume":"11","author":[{"given":"Shih Chi","family":"Peng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David Shan Hill","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai Che","family":"Tung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun Cheih","family":"Chao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien Hua","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung Jen","family":"Chuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan Yi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2010,6,8]]},"reference":[{"issue":"5400","key":"3765_CR1","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1126\/science.283.5400.381","volume":"283","author":"US Bhalla","year":"1999","unstructured":"Bhalla US, Iyengar R: Emergent properties of networks of biological signaling pathways. 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