e been tested in our Y2H experiment, the human ORFeome v3. 1. The corrected p value was computed using the Benjamini Hochberg multiple testing necessary correction. We limited our results to GO annotations and pathways for which at least two Hoxa1 targets were annotated for. To estimate the significance of indirect targets enrich ment we ran 100,000 simulations for which the identity of the direct targets was randomized. The interactors of these targets were identified in an unbiased protein protein interaction network, to avoid study bias inherent to literature curation. Interactors belonging to each pathway were counted, and the resulting distribu tion compared to the observed counts. An empirical False Discovery Rate determined the significance of the enrichment, with the FDR computed as the proportion of random trials giving at least the observed number of indirect targets in the analyzed pathway.

The FDR was corrected for multiple testing using the Bonferroni correction. Pathways with a corrected FDR 0. 05 and at least two observed proteins were considered significant. Secretory leukocyte protease inhibitor is a mem ber of the chelonianin class of serine protease inhibitors, and is predominantly expressed in secretory epithelial cells of mucosal surfaces, immune cells and has been identified in various tissues. Among serine protei nase inhibitors, SLPI is considered as alarm proteinase inhibitor that is upregulated during infection or inflam mation to compensate for high human neutrophil elas tase. The C terminus of SLPI primarily inhibits human elastase, but is capable of inhibiting other serine proteinases such as tryptase and cathepsin G.

In addition to its function as an antiprotease, SLPI pos sesses antimicrobial activity against several bacteria and fungi. Furthermore, it was shown that SLPI con trols cell proliferation by regulation of growth associated genes such as cyclin D and transforming growth factor Drug_discovery b1, modifies the activation of macrophages and regulates the LPS induced activation of the tran scription factor nuclear factor kappa B. SLPI deficient mice provided evidence for functional involvement of SLPI in wound healing and lipopo lysaccharide mediated inflammation. In con text to its role as alarm proteinase inhibitor, SLPI was found to be differentially regulated in inflammatory dis eases and cancer.

Increased expression or elevated serum levels of SLPI were reported in human sepsis and experimental endotoxemia, febrile patients, Wegnerss granulomatosis, gastric cancer and pulmonary infection. tech support In contrast, other bacterial or viral infections in lung, stomach and cervical epithelial cells were found to be associated with decreased SLPI levels. The underlying mechanisms responsible for the different regulation of SLPI have not been identified, but most likely both microbial and host factors contribute to the up or downregulation of SLPI in the various diseases. Notably, the reduction of SLPI levels correlated inversely with the severit