Early response cytokines and innate immunity: Essential roles for TNF receptor 1 and type I IL-1 receptor during Escherichia coli pneumonia in mice

The early response cytokines, TNF and IL-1, have overlapping biologic effec ts that may function to propagate, amplify, and coordinate host responses t o microbial challenges. To determine whether signaling from these early res ponse cytokines is essential to orchestrating innate immune responses to in trapulmonary bacteria, the early inflammatory events induced by instillatio n of Escherichia coli into the lungs were compared in wild-type (WT) mice a nd mice deficient in both TNF receptor 1 (TNFR1) and the type I TL-1 recept or (IL1R1), Neutrophil emigration and edema accumulation induced by E, coli were significantly compromised by TNFR1/IL1R1 deficiency. Neutrophil numbe rs in the circulation and within alveolar septae did not differ between WT and TNFR1/IL1R1 mice, suggesting that decreased neutrophil emigration did n ot result from decreased sequestration or delivery of intravascular neutrop hils. The nuclear translocation of NF-KB and the expression of the chemokin e macrophage inflammatory protein-2 did not differ between WT and TNFR1/IL1 R1 lungs. However, the concentration of the chemokine KC was significantly decreased in the bronchoalveolar lavage fluids of TNFR1/IL1R1 mice compared with that in WT mice. Thus, while many of the molecular and cellular respo nses to E, coli in the lungs did not require signaling by either TNFR1 or I L1R1, early response cytokine signaling was critical to KC expression in th e pulmonary air spaces and neutrophil emigration from the alveolar septae.