Increased susceptibility of mice to Salmonella infection following in vivo treatment with the substance P antagonist, spantide II.

Abstract

Successful resolution of salmonellosis in naive mice depends in large part upon IL-12-induced IFN-gamma production to eliminate this intracellular pathogen of macrophages. In the present study we questioned the contribution that expression of substance P receptors makes to the protective response following oral inoculation with a lethal dose of Salmonella. Such a relationship was suggested when oral inoculation with Salmonella induced rapid and dramatic increases in substance P receptor mRNA expression within Peyer's patches and mesenteric lymph nodes and subsequently in the spleen. The importance of substance P receptor expression in vivo was further suggested by pretreatment of mice with the substance P antagonist, spantide II, before oral inoculation with Salmonella. Mice pretreated with spantide II and then orally inoculated developed advanced salmonellosis and had significantly reduced survival rates compared with mice pretreated with a control peptide. Treatment with spantide II significantly reduced early Salmonella-induced IL-12p4O and IFN-gamma mRNA expression at mucosal sites, suggesting a mechanism for the reduced ability of spantide II-treated mice to resist this pathogen. Increased susceptibility to salmonellosis was not due to 1) spantide II-induced alterations in the uptake of this pathogen from the gut, 2) global spantide II-mediated immune suppression, or 3) nonsubstance P receptor-mediated effects of spantide II on macrophages. The ability of Salmonella to induce substance P receptor expression on cultured macrophages suggested that one mechanism for resistance against this intracellular pathogen might be a direct effect of substance P on this cell population.

• Authors: T Kincy-Cain, K L Bost
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 157 Issue 1 Pg. 255-64 (Jul 01 1996) ISSN: 0022-1767 [Print] United States
• PMID: 8683123 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• RNA, Messenger
• Receptors, Neurokinin-1
• spantide II
• Interleukin-12
• Substance P
• Interferon-gamma

Topics

• Administration, Oral
• Amino Acid Sequence
• Animals
• Base Sequence
• Cells, Cultured
• Disease Susceptibility
• Female
• Interferon-gamma (biosynthesis)
• Interleukin-12 (biosynthesis)
• Leukocytes, Mononuclear (drug effects, immunology)
• Lymphocyte Activation (drug effects)
• Macrophage Activation (drug effects)
• Mice
• Mice, Inbred BALB C
• Molecular Sequence Data
• RNA, Messenger (biosynthesis)
• Receptors, Neurokinin-1 (biosynthesis, genetics)
• Salmonella Infections, Animal (etiology, immunology, mortality)
• Substance P (administration & dosage, analogs & derivatives, antagonists & inhibitors, biosynthesis, genetics, pharmacology)