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Regulation of endothelial cell adhesion molecule expression in an experimental model of cerebral malaria
Phillipe R Bauer1, Henri C Van Der Heyde, Guang Sun
1Departments of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
Objective:
Plasmodium falciparum malaria in humans and animal models of this disease have revealed changes in the infected host that are consistent with a systemic inflammatory response. Although it has been proposed that endothelial cell adhesion molecules (CAM) contribute to the adhesive interactions of Plasmodium-infected erythrocytes and immune cells with vascular endothelial cells, ECAM expression has not been systematically studied in Plasmodium-infected animals.
Methods:
In this study, the dual radiolabeled monoclonal antibody method was used to quantify the expression of different ECAMs (ICAM-1, VCAM-1, P-selectin, E-selectin) in different regional vascular beds of Plasmodium berghei ANKA-inffected mice (PbA), a well-recognized model of human cerebral malaria. The roles of T lymphocytes and certain cytokines (TNF-alpha, IL-12, IFN-gamma) in mediating the infection-induced expression of ICAM-1 and P-selectin were assessed by using relevant mutant mice.
Results:
Wild-type (WT) mice exhibited highly significant increases in the expression of ICAM-1, VCAM-1, and P-selectin (but not E-selectin) in all vascular beds on the 6th day of PbA infection. The PbA-induced upregulation of ICAM-1 was significantly blunted in mice that were either deficient in IFN-alpha, IL-12 (but not TNF1b) or T lymphocytes (Rag-1 deficiency); however, these responses were tissue specific.
Conclusions:
These findings indicate that vascular endothelial cells in most regional circulations assume an inflammatory phenotype and that cytokines and immune cells mediate this response in a tissue-specific manner.
Insights
Malaria infection causes inflammation in blood vessels, increasing cell adhesion molecules. Immune cells and cytokines mediate this response, which varies by tissue.
Area of Science:
- Immunology
- Pathology
- Vascular Biology
Background:
- Malaria infection induces systemic inflammation.
- Endothelial cell adhesion molecules (ECAMs) are implicated in Plasmodium-infected erythrocyte and immune cell interactions with endothelium.
- ECAM expression in Plasmodium-infected animals remains understudied.
Purpose of the Study:
- To systematically study ECAM expression in a mouse model of malaria.
- To investigate the role of T lymphocytes and cytokines in mediating infection-induced ECAM expression.
Main Methods:
- Quantified ECAM expression (ICAM-1, VCAM-1, P-selectin, E-selectin) using dual radiolabeled monoclonal antibodies in Plasmodium berghei ANKA (PbA)-infected mice.
- Assessed the roles of T lymphocytes and cytokines (TNF-alpha, IL-12, IFN-gamma) in ECAM upregulation using mutant mice.
Main Results:
- PbA infection significantly increased ICAM-1, VCAM-1, and P-selectin expression in wild-type mice.
- Upregulation of ICAM-1 was reduced in mice deficient in IFN-gamma, IL-12, or T lymphocytes.
- These responses demonstrated tissue-specific regulation.
Conclusions:
- Vascular endothelial cells adopt an inflammatory phenotype during malaria infection.
- Cytokines and immune cells are key mediators of this inflammatory response.
- The inflammatory response is tissue-specific.