Lymphocyte Function-Associated Antigen-1 Blockade by Statins: Molecular Basis and Biological Relevance

Weitz‐Schmidt, Gabriele

doi:10.1080/10623320303360

Cited by 35 publications

(28 citation statements)

References 39 publications

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“…The interaction between activated LFA-1 and the intracellular adhesion molecule-1 (ICAM-1) providing signals for both leukocyte migration and costimulation is also blocked by statins. Other adhesion molecules in monocytes and T cells have been shown to be inhibited by statins, ICAM-1, CD11b, CD18, and CD49 (Weitz-Schmidt, 2003). A recent study in patients with acute coronary syndrome confirmed the reduced levels of adhesion molecules ICAM-1 and vascular cell adhesion molecule-1 after short-term atorvastatin preload (Patti et al, 2010).…”

Section: Statin Effects Onmentioning

confidence: 57%

“…Statin Effects on Adhesion Molecules. Another component of the immunological synapse selectively blocked by the statins is the lymphocyte function-associated antigen-1 (LFA-1) (Weitz-Schmidt, 2003), an ␣/␤ heterodimeric receptor belonging to the ␤2 integrin subfamily that plays a central role in lymphocyte homing and leukocyte trafficking. Initially, lovastatin was shown to block LFA-1 by binding to the allosteric site of the extracellular I domain on the ␣ L chain (therefore known as the lovastatin site).…”

Section: Statin Effects Onmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Gazzerro

Proto²,

Gangemi³

et al. 2011

Pharmacol Rev

399

384

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Section: Statin Effects Onmentioning

confidence: 57%

Section: Statin Effects Onmentioning

confidence: 99%

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Gazzerro

Proto²,

Gangemi³

et al. 2011

Pharmacol Rev

399

384

View full text Add to dashboard Cite

“…Beyond lowering cholesterol and inhibiting the isoprenoids, the pleiotropic effects of statins may also be due to inhibition of MA-independent pathways, that is, independent of HMG-CoA reductase inhibition (19)(20)(21). Therefore, we sought to determine whether the effects of simvastatin in our experimental model of asthma are modulated by MA inhibition.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Inhibits Airway Hyperreactivity

Zeki

Franzi

Kenyon

2009

Am J Respir Crit Care Med

109

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Rationale: Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism. Objectives: To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition. Methods: BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure. Measurements and Main Results: Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P , 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P , 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-a levels were all reduced by treatment with simvastatin (P , 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P 5 0.0001). Conclusions: Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma.

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“…The interaction of leukocyte function-associated antigen-1 (LFA-1) 4 and intercellular adhesion molecules (ICAMs) plays a key role in the immune system and in the development of arteriosclerosis, autoimmune diseases, and inflammation (1)(2)(3)(4)(5). Further understanding of the LFA-1 activation mechanism is necessary for the development of novel therapeutics that could modulate the immune system (6,7).…”

mentioning

confidence: 99%

A Mechanism for Antibody-mediated Outside-in Activation of LFA-1

Carreño

Şen

et al. 2008

Journal of Biological Chemistry

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MEM83 is an inserted domain (I-domain)-specific antibody that up-regulates the interaction of LFA-1 with ICAM-1 through an outside-in activation mechanism. We demonstrate here that there is no change in the affinity of the MEM83 antibody for the I-domain in either its low (wild-type) or high affinity form and that MEM83 does not enhance the binding of the wild-type I-domain to ICAM-1. Furthermore, we show that the antibody acts as an activating agent to induce LFA-1/ICAM-1-dependent homotypic cell aggregation only as an IgG, but not as a Fab fragment. On the basis of these data, we propose an avidity-based mechanism that requires no direct activation of the LFA-1 I-domain by the binding of the antibody; rather, activation is enhanced when there is an interaction with both arms of the IgG. A molecular model of the antibody interaction with LFA-1 illustrates the symmetry and accessibility of the two MEM83 epitopes across the LFA-1/ICAM-1 heterotetramer. We hypothesize that MEM83 stabilizes adjacent LFA-1 molecules in their active form by the free energy that is gained from the binding of the I-domains to each arm of the IgG. This leads to stabilization of the open state of the integrin and outside-in signaling. Our model supports a mechanism in which both affinity and avidity regulation are required in the activation of LFA-1.The interaction of leukocyte function-associated antigen-1 (LFA-1) 4 and intercellular adhesion molecules (ICAMs) plays a key role in the immune system and in the development of arteriosclerosis, autoimmune diseases, and inflammation (1-5). Further understanding of the LFA-1 activation mechanism is necessary for the development of novel therapeutics that could modulate the immune system (6, 7). Inhibitors that stabilize the inactive form or block the active form of LFA-1 suppress immune responses and may prevent inflammatory and autoimmune disease (8 -10). Similarly, up-regulation of LFA-1 can be used to enhance immune responses (11-13) and may have roles in restoring T cell function in human immunodeficiency virusimmunocompromised individuals (14) or in overcoming tumor-specific toleration (15).Activation of the integrin LFA-1 results in a rapid and reversible increase in affinity for its ligands, . ICAM-1-3 regulate T cell activation (13) and leukocyte homing (20, 21); ICAM-4 is a red blood cell-specific ligand that can interact with a several ␤2/CD18 integrins (22); and ICAM-5 plays a role in leukocyte recruitment to neurons in the central nervous system (19). In T cells, LFA-1 and ICAM-1 act as costimulatory molecules to the peptide/major histocompatibility complex (23,24). The role of LFA-1 and ICAM-1 interaction is critical to the formation of the immunological synapse, and aberrant activation or expression of LFA-1 may lead to selectively disabled T cell receptor clustering (25) or the development of autoimmune diseases (26,27).Recognition and binding of its ICAM-1 ligand by LFA-1 are mediated through the inserted domain (I-domain) in its ␣-subunit; this forms a heterotetrameric comple...

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Lymphocyte Function-Associated Antigen-1 Blockade by Statins: Molecular Basis and Biological Relevance

Cited by 35 publications

References 39 publications

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Simvastatin Inhibits Airway Hyperreactivity

A Mechanism for Antibody-mediated Outside-in Activation of LFA-1

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