Lipopolysaccharide nonresponder cells: the C3H/HeJ defect.
Since its initial discovery as endotoxin resistant, the C3H/HeJ mouse has been extensively studied and used as a comparative model to help reveal the mechanism under genetic control which governs host responses to endotoxin. Most of the research has focused on the B lymphocyte and macrophage of this strain which fail to be activated by LPS. Recently, specific LPS binding proteins have been isolated on lymphocytes and other cells; however a receptor which transduces an activation signal has not been isolated as yet from responder cells which is missing or altered on C3H/HeJ nonresponder cells. Investigations into the signal transduction pathways used by C3H/HeJ B cells when they are activated by a protein mitogen have been found to be similar to those used by LPS responder cells when activated by LPS. Protein kinase C and tyrosine kinase, which phosphorylate signal proteins in cells have been found to be operative in C3H/HeJ and C3H/OuJ B cells. In both cases, DNA synthesis is shut off by either PKC or PTK blockade; however, PTK inhibition will also block activation of PKC stimulated DNA synthesis, indicating tyrosine kinase initiated phosphorylation may regulate the PKC signal pathway. Further analysis of the proteins that are phosphorylated in LPS responder and LPS nonresponder B cells is needed before conclusions can be drawn as to whether the defect in C3H/HeJ cells resides in the signal pathway leading to gene activation and proliferation. Nevertheless, the notion of a missing or defective signal receptor still remains as a working hypothesis to explain C3H/HeJ cell hyporesponsiveness to LPS. Isolation of the Lpsn gene and its product will provide the evidence needed for a clearer understanding of how LPS reacts with cells.
Sultzer
B M
BM
Department of Microbiology and Immunology, State University of New York Health Science Center, Brooklyn.
Castagna
R
R
Bandekar
J
J
Wong
P
P
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D004731:Endotoxins / Q000276:immunology; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H / Q000235:genetics* / Q000276:immunology; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology
D004731:Endotoxins; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D004247:DNA; D011494:Protein Kinases