Cells react to microorganisms by activating innate immune responses that rely on recognition of non-self molecular patterns, such as the bacterial cell wall component lipopolysaccharide (LPS). Exposure of the adherent neutrophil to the LPS component of gram negative bacteria results in an integrated response involving activation of JNK MAP kinase, which is involved in a variety of downstream functional effects that may contribute to the pathogenesis of ARDS. We propose that the adherent neutrophil assembles a signaling complex involving activation of tyrosine kinase Syk, and utilizes adaptor molecules, particularly SLP-76, previously known in mediating signal transduction in the lymphocyte, but never previously implicated in neutrophil signal transduction. We further suggest that the JNK pathway is regulated not only in the activation of membrane proximal adaptors, but is also influenced by cross-talk between p38 MAP kinase and JNK. We suggest that p38 activates PP2A, a phosphatase that inactivates MKK4. Using a variety of techniques to detect molecular interactions and modify expression levels in human and murine neutrophils, and transfectable neutrophilic cell lines we will address 2 major specific aims: 1) To define the molecular mechanisms by which the LPS receptor complex activates JNK in the adherent neutrophil, and 2) To determine the mechanisms by which p38 regulates activation of the JNK pathway. The results of these investigations will highlight novel aspects of neutrophil signal transduction in response to LPS that lead to activation of JNK, and provide insights into the assembly of multi-component signaling complexes whose interactions will provide new approaches to modulation.
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