Requisite Role for Interleukin-4 in the Acceleration of Fatty Streaks Induced by Heat Shock Protein 65 or Mycobacterium tuberculosis

• Published in: Circulation research 2000-06, Vol.86 (12), p.1203-1210
• Main Authors: George, Jacob, Shoenfeld, Yehuda, Gilburd, Boris, Afek, Arnon, Shaish, Aviv, Harats, Dror
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - analysis; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase - metabolism; Arteriosclerosis - blood; Arteriosclerosis - immunology; Atherosclerosis (general aspects, experimental research); Bacterial Proteins; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Division; Chaperonin 60; Chaperonins - immunology; Chaperonins - physiology; Cholesterol - blood; Female; Immunization; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-4 - biosynthesis; Interleukin-4 - deficiency; Interleukin-4 - genetics; Interleukin-4 - physiology; Lymphocytes - pathology; Macrophages, Peritoneal - enzymology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout - genetics; Mycobacterium tuberculosis - immunology; Reference Values
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.86.12.1203

Atherosclerotic lesions can be induced in rabbits and mice immunized with heat shock protein 65 (HSP65). In the current study, we investigated the role of interleukin (IL)-4 in the HSP65- and Mycobacterium tuberculosis (MT)–induced models that exhibit an inflammatory phenotype. Fatty streak formation in IL-4–knockout (IL-4 KO) mice immunized with HSP65 or MT was significantly reduced when compared with lesions in wild-type C57BL/6 mice. However, when injected with control (HSP-free) adjuvant, no differences were evident in the lesion size between wild-type and the IL-4 KO mice. Next, we studied comparatively the extent of humoral and cellular immune responses to HSP65 in the IL-4 KO and wild-type mice, as those are thought to be influential in murine atherosclerosis. Anti-HSP65 antibody levels were reduced in the HSP65-immunized IL-4 KO mice as compared with their wild-type littermates, whereas no differences were evident between the groups with respect to the primary cellular immune response to HSP65. Other than the absence of IL-4 in the knockout mice, the pattern of secreting cytokines interferon-γ and IL-10 in concanavalin A–primed splenocytes was similar between the groups. HSP65-primed inguinal lymphocytes from IL-4 KO mice immunized with HSP65 secreted higher levels of interferon-γ (previously shown to be proatherogenic in vivo) as compared with their wild-type controls. 12-/15-Lipoxygenase expression, known to be regulated by IL-4 and to contribute to murine atherosclerosis, in the lesions was not influenced by the immunization protocol used or by IL-4 disruption. Thus, IL-4 may prove a principal cytokine in the progression of early “inflammatory” atherosclerotic lesions and may serve as a target for immunomodulation. (Circ Res. 2000;86:1203-1210.)