Lipopolysaccharide nonresponder cells: the C3H/HeJ defect

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The C3H/HeJ mouse is endotoxin resistant, serving as a model to study genetic control of host responses to lipopolysaccharide (LPS).
• Research primarily focuses on B lymphocytes and macrophages, which are not activated by LPS in this strain.
• A specific LPS receptor that transduces activation signals has not been identified in responder cells or found to be altered in C3H/HeJ nonresponder cells.

Purpose of the Study:

• To investigate the signal transduction pathways in C3H/HeJ B cells activated by a protein mitogen.
• To compare these pathways with those in LPS-responder cells activated by LPS.
• To explore the role of protein kinase C (PKC) and tyrosine kinase (PTK) in B cell activation and proliferation.

Main Methods:

• Investigated signal transduction pathways in C3H/HeJ B cells using a protein mitogen.
• Compared these pathways to LPS-activated pathways in responder cells.
• Examined the effects of protein kinase C (PKC) and tyrosine kinase (PTK) inhibition on DNA synthesis.

Main Results:

• Signal transduction pathways in C3H/HeJ B cells activated by a protein mitogen are similar to LPS-responder cells activated by LPS.
• Both PKC and PTK are operative in C3H/HeJ and C3H/OuJ B cells.
• PTK inhibition blocks PKC-stimulated DNA synthesis, suggesting PTK regulates the PKC pathway.

Conclusions:

• A missing or defective LPS signal receptor remains a working hypothesis for C3H/HeJ hyporesponsiveness.
• Further analysis of phosphorylated proteins is needed to determine if the defect lies in the signal pathway for gene activation and proliferation.
• Isolation of the Lpsn gene and its product is crucial for understanding LPS-cell interactions.