The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- mice.

• Both innate and adaptive immunity contribute to the progression of inflammatory-fibrotic lesions of atherosclerosis. Although platelet-derived growth factor (PDGF)-B has been investigated as a stimulant of smooth muscle cells in vascular diseases, its effects on the immune response during disease have not been evaluated in vivo. We used hematopoietic chimeras generated after lethal irradiation of ApoE-/- recipients to test the role of PDGF in atherosclerosis. Monocyte accumulation in early atherosclerotic lesions increased 1.9-fold in ApoE-/-/PDGF-B-/- chimeras. Lymphocytes from null chimeras showed a 1.6- to 2.0-fold increase in the number of activated CD4(+) T cells and a 2.5-fold elevation of interferon-gamma-secreting CD4(+) T cells on ex vivo challenge with modified low-density lipoprotein. Splenocyte transcript levels were also altered with a twofold decrease in interleukin-10 and 1.7- and 3.0-fold increases in interleukin-18 and CCR 5, respectively. These cellular and molecular changes were consistent with a shift to a proinflammatory phenotype in null chimeras. Our data also demonstrated for the first time the presence of a recently discovered family of negative regulators of innate and adaptive immunity, the suppressors of cytokine signaling (SOCS), in developing atherosclerotic lesions. Thus, our studies identify two independent negative immune regulatory pathways-PDGF-B and SOCS-that may help limit lesion expansion.

Nyckelord

Animals

Apolipoproteins E

deficiency

genetics

Arteriosclerosis

complications

genetics

immunology

pathology

Blood Cells

metabolism

Bone Marrow Cells

metabolism

Carrier Proteins

metabolism

Chimera

Gene Expression Profiling

Genetic Predisposition to Disease

Inflammation

etiology

Ligands

Lymphocyte Activation

Macrophages

metabolism

Male

Mice

Mice

Inbred C57BL

Mice

Knockout

Monocytes

pathology

Platelet-Derived Growth Factor

metabolism

Proto-Oncogene Proteins c-sis

deficiency

genetics

RNA

Messenger

metabolism

Receptor

Platelet-Derived Growth Factor alpha

genetics

Repressor Proteins

metabolism

Suppressor of Cytokine Signaling Proteins

T-Lymphocytes

immunology

Transcription Factors

metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)