Abstract The transcription factor NF-B is an essential regulator of the innate immune response which functions as the first line of defense against infections. Activation of the innate immune response by bacterial lipopolysaccharide (LPS) triggers production of tumor necrosis factor-alpha (TNF) followed by interleukin-1 (IL-1). The interleukin-1 receptor associated kinase 1 (IRAK-1) is an integral component of the LPS, TNF and IL-1 signaling pathways that regulate NF-B. Thus we hypothesized that IRAK-1 coordinates cellular NF-B responses to LPS, TNF and IL-1. In contrast to TNF where IRAK-1 subcellular localization does not change, treatment with LPS or IL-1 leads to a loss in cytoplasmic IRAK-1 with a coordinate increase in plasma membrane associated modified IRAK-1. In fibroblasts lacking the type I TNF receptor (TNF RI) IRAK-1 turnover is altered and modification of IRAK-1 in the plasma membrane is decreased in response to LPS and IL-1, respectively. When NF-B controlled gene expression is measured fibroblasts lacking TNF R1^-/- are hyperresponsive to LPS; whereas a more variable response to IL-1 is seen. Further analysis of the LPS response revealed that plasma membrane associated IRAK-1 is found in Toll 4, IL-1 and type I TNF receptor containing complexes. The data presented herein suggest a model whereby the TNF R1-IRAK-1 interaction integrates the cellular response to LPS, TNF and IL-1 culminating in a cell poised to activate TNF dependent NF-B controlled gene expression. In the absence of TNF RI dependent events, exposure to LPS or IL-1 leads to hyperactivation of the inflammatory response.