In addition, specific anti-apoptosis, cell adhesion and extracellular matrix proteins were only down-regulated in NEC patients, possibly revealing the different nature of bowel injury and/or severity of inflammation compared with SIP. Further validation of selected targets confirmed up-regulation of IL-6, Ang-2, sIL1-RII and suPAR in NEC infants compared with gestational age-matched controls, but the circulating level of sErbB3 was significantly decreased compared with SIP infants. mRNA expressions of IL-6, IL1-RII and uPAR were up-regulated in resected bowel tissues from NEC infants and in accordance with changes in plasma proteins. This indicated that immunomodulation had occurred at the tissue and cellular levels of the affected bowel, which could have contributed to their corresponding increased levels in the plasma. In a model of human fetal enterocytic cell line FHs-74 Int, Ang-2, IL1-RII and uPAR expressions were significantly induced by the combined treatment with LPS and PAF, again suggested that these genes could act synergistically and play a pivotal role in disease development and progression of NEC. Using cytokine array as a hypothesis-free approach, we provided specific profiles of plasma immunoregulatory proteins in NEC and SIP infants. Our findings are in line with other studies on cytokines, showing regulation of pro- and anti-inflammatory, and repair-associated proteins in NEC infants, TH-302 including IL-6, IL8, IL-10, TNF, ENA-78, matrix metalloprotease-9, GRO, MCP-1 and IGF-1. We have also discovered novel immunoregulatory proteins such as Ang-2, ErbB3 and uPAR, which have not been previously described in NEC or SIP. Importantly, there have not been any comprehensive data on immunoregulatory proteins reported in SIP. Our plasmatic protein profile thus represents the basic information platform for further mechanistic investigation of this disease. Despite sharing many common dysregulated immunomodulatory proteins in the two conditions, some appeared to be more specific to either NEC or SIP, thus reflecting differences regarding the etiology, pathophysiology and severity of inflammation of the two conditions. We validated IL-6, Ang-2, IL1-RII and uPAR in their soluble forms as well as in intestinal tissues and in a fetal enterocyte model, suggesting that the systemic dysregulation of these proteins not only occurred at the plasma level, but also at the cellular level of inflamed bowel tissues and enterocytes. The evidence suggested up-regulation of IL-6, Ang-2, sIL1-RII and suPAR in NEC infants, whereas sErbB3 was significantly higher in the plasma of SIP compared with NEC infants. Despite changes of immunoregulatory proteins were observed in the plasma of SIP patients, the targeted gene levels in the bowel specimens were not different from tissues of surgical control subjects. This might reflect minimal intestinal inflammation due to the localized nature of bowel perforation. The exaggerated up-regulation of immunomodulatory proteins in NEC infants represented imbalance of the inflammatory cascade, which could lead to necrosis, apoptosis and severe tissue damage. This could account for the high morbidity and mortality rate in NEC compared with SIP infants. Of clinical interest, further investigation on validating these dysregulated proteins in a cohort study, either individually or in combination as diagnostic biomarkers, might reveal their usefulness for early differentiation of NEC from SIP patients.