Protective Effects of Angiotensin II Interruption: Evidence for Antiinflammatory Actions

Nigel J. Dagenais, B.Sc.(Pharm.); Fakhreddin Jamali, Ph.D.

Disclosures

Pharmacotherapy. 2005;25(9):1213-1229. 

In This Article

Balance of T-Helper 1 and 2 Cells

The CD4+ T cells conduct adaptive immune responses as a reaction to foreign antigen. In general, two distinct subpopulations of CD4+ T-helper cells exist due to the different cytokine arrays produced. These are the T-helper (Th)1 and Th2 phenotypes. The Th1 cells produce predominantly IL-2, IFN-γ, and TNF-α, which induce cellular immune responses and activate macrophages. The Th2 phenotype produces mainly IL-4, IL-5, IL-10 and IL-13, which are important in aiding B-cell activation and antibody production.[14,15] As a rule, Th1 cytokines suppress Th2 and vice versa; thus, once a particular T-helper cell immune response is established (Th1 or Th2), the polarized subtype tends to persist through positive feedback mechanisms.

In addition to various well-established risk factors for atherosclerosis, such as hypertension, obesity, dyslipidemia, diabetes mellitus, and smoking, inflammatory biomarkers such as C-reactive protein have emerged as independent risk factors in patients with cardiovascular disease[19] and in healthy individuals.[20] Similar data have implicated TNF-α[21] and IL-6[22] with increased risk. However, evidence suggests that the type of inflammation, particularly an imbalance toward a Th1 rather than Th2 polarization, may also have important implications in atherogenesis. The presence of CD4+ T lymphocytes and macrophages (i.e., Th1-dependent leukocytes) in significant numbers in all stages of atherosclerotic plaque suggests an underlying Th1 inflammatory process.[23] Interleukin-12, an inducer of the Th1 phenotype, is plentiful in human plaque.[24] In addition, the Th1 cytokine IFN-γ is highly expressed in human and murine atherosclerotic plaque. The presence of IFN-γ in plaque may be particularly important, since this cytokine activates macrophages to produce more cytokines and free radicals.

Moreover, IFN-γ also stimulates endothelial cells to express adhesion molecules, thereby perpetuating the inflammatory process. Direct administration of IFN-γ has enhanced atherosclerotic lesion development in mice.[15] Conversely, IFN-γ receptor knock-out mice demonstrated reduced atherosclerosis development. Pentoxifylline, which inhibits the Th1 response, has also reduced atherogenesis in vivo.[25] Since IL-10 can suppress Th1 cytokines and IFN-γ suppresses IL-10, the balance between Th1 and Th2 cytokines may contribute to the degree of plaque development. Interleukin-10 knock-out mice showed greater plaque progression, whereas IFN-γ receptor knock-out mice show less lesion progression, which supports this theory.[15] Altogether, the Th1 polarization seems necessary for atherosclerosis induction and progression.

However, the Th1 phenotype is not just proatherogenic. Interleukin-1β and TNF-α also contribute to plaque instability through induction of matrix metalloproteinases. These enzymes digest collagen in plaque, thus weakening the fibrin cap and increasing susceptibility to fracture, downstream thrombosis, and subsequent ischemia (e.g., myocardial infarction).[26,27] Of interest, IL-4 and IL-10 reduce matrix metalloproteinase synthesis, suggesting the importance of Th2 cytokines in preventing acute coronary syndromes.[26] Thus, a switch from a Th1 to a Th2 polarization may not only reduce plaque progression but may also increase plaque stability, reducing the risk of rupture and subsequent thrombosis.

Clinical evidence supports the theory of a Th1-Th2 imbalance: patients with unstable angina demonstrate decreased IL-10 serum concentrations.[28] In addition, elevated IL-10 serum concentrations are predictive of improved endothelial function (e.g., improved vascular relaxation) in patients with coronary artery disease.[29] In one study, IL-10 and C-reactive protein were measured at baseline and at hospital discharge in 547 patients after an unstable angina attack.[30] Elevated IL-10 concentrations at discharge after acute coronary syndromes were associated with a lower cardiac risk at 6-month follow-up. In fact, elevated IL-10 serum concentrations were protective even in patients with elevated C-reactive protein levels. This clinical finding is further evidence that mortality in patients with cardiovascular disease is not simply correlated with elevated proinflammatory mediators (e.g., C-reactive protein). More important, mortality is inversely associated with a healthy balance of antiinflammatory mediators. Therefore, drugs that can influence the Th1-Th2 balance may have profound effects on cardiovascular disease progression.

A similar paradigm of a polarized Th1 response is found in patients with rheumatoid arthritis; cloned CD4+ T cells from human synovium widely exhibit a Th1 cytokine array with large amounts of IFN-γ production and minimal or absent IL-4.[31] Accordingly, significantly reduced IL-4 and IL-10 messenger RNA concentrations are found in synovial mononuclear cells of patients with rheumatoid arthritis. Furthermore, therapy with disease-modifying drugs such as methotrexate and cyclosporine has resulted in downregulation of IFN-γ production and elevated Th2 cytokine concentrations, such as IL-4.[32] This suggests that the antiinflammatory activity of such treatment may be due partly to induction of Th2 cytokines, thus shifting the Th1-Th2 balance toward Th2 polarization.

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