**5.3 Role of cytokines and chemokines**

NEC is associated with increased expression of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6, IL-8/CXC-motif ligand 8 (CXCL8), IL 10 monocyte chemoattractant protein-1/CC-motif ligand (CCL)-2, macrophage inflammatory protein-1β/CCL3, and C-reactive protein in plasma and affected tissues [32]. These cytokines can disrupt the epithelial barrier and augment intestinal injury. Serum levels of cytokines/chemokines are elevated in NEC, and increased TLR4 and abnormal IkB/NFkB suggest excessive abnormal immunological response [33–35]. Lower blood TGF-β and interleukin (IL)-2 and higher IL-8 levels are found in ELBW infants with NEC. A developmental immaturity is noted in IkB expression, the molecule that inhibits cytokines activation via NFkB in NEC. Recently the role of toll-like receptor 4 (TLR4) signaling in the pathogenesis of NEC has been highlighted. Hypoxia, infection, and prematurity accentuate the expression of TLR4 in the intestinal mucosa. TLR4 is subsequently activated by enteric bacteria, triggering an inflammatory cascade which results in increased gut mucosal injury and reduced epithelial repair. Activation of cytoplasmic innate immune receptors, NOD2 and TLR9 leads to inhibition of TLR4, with restoration of the intestinal epithelial barrier and reduction in severity of NEC in experimental models. Other factors implicated in pathogenesis of NEC are platelet-activating factor, nitric oxide, reactive oxygen species, and transforming growth factors. However, despite success in animal model systems, no significant improvement in treatment and outcomes of NEC has been achieved due to an incomplete understanding of the developing immune system in premature infants and inability to replicate them in animal models [32].
