Proteasome inhibition: A novel mechanism to combat asthma

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Presentation transcript:

Proteasome inhibition: A novel mechanism to combat asthma Peter J. Elliott, PhDa, Christine S. Pien, MSa, Teresa A. McCormack, PhDa, Ian D. Chapman, PhDb, Julian Adams, PhDa Journal of Allergy and Clinical Immunology Volume 104, Issue 2, Pages 294-300 (August 1999) DOI: 10.1016/S0091-6749(99)70369-6 Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 1 Effect of intravenous administration of dexamethasone on ear swelling in mice induced by treatment with DNFB. Dexamethasone was given 30 minutes before challenge. Values are given as percent of vehicle (Veh) -treated mice ± SEM. *P < .01 with respect to vehicle-treated animals (n = 8 to 18/group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 2 Effect of intravenous administration of the proteasome inhibitor β-lactone on ear swelling in mice induced by treatment with DNFB. β-Lactone was given 30 minutes before challenge. Values are given as percent of vehicle (Veh) -treated mice ± SEM. *P < .01 with respect to vehicle-treated animals (n = 5 to 201/group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 3 Effect of intravenous administration of the proteasome inhibitor PS-519 on ear swelling in mice induced by treatment with DNFB. PS-519 was given 30 minutes before challenge. Values are given as percent of vehicle (Veh) -treated mice ± SEM. *P < .01 with respect to vehicle-treated animals (n = 26 to 131/group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 4 Effect of intravenous administration of the proteasome inhibitor β-lactone (Lact) in combination with dexamethasone (Dex) on ear swelling in mice induced by treatment with DNFB. Both drugs were given 30 minutes before challenge. Values are given as percent of vehicle (Veh)-treated mice ± SEM. *P < .05 with respect to vehicle-treated animals; #P < .05 with respect to dexamethasone-treated animals (n = 16 /group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 5 Effect of intratracheal administration of the proteasome inhibitor PS-519 on infiltration of leukocytes into the lungs of Brown Norway rats challenged with ovalbumin. PS-519 was given 1 hour before and 24 and 48 hours after challenge. Cell number values are given as means ± SEM. *P < .05 and **P < .01 with respect to vehicle (Veh)-treated animals (n = 10/treatment group and n = 5 for the naive group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 6 Effect of intratracheal administration of the proteasome inhibitor PS-519 on eosinophilia in lungs of Brown Norway rats challenged with ovalbumin. PS-519 was given 1 hour before and 24 and 48 hours after challenge. Cell number values are given as means ± SEM. *P < .05 and **P < .01 with respect to vehicle (Veh)-treated animals (n = 10/treatment group and n = 5 for the naive group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 7 Effect of intratracheal administration of the proteasome inhibitor PS-519 on eosinophilia in lungs of Brown Norway rats challenged with ovalbumin in combination with the corticosteroid budesonide (0.1 mg/kg). PS-519 was given 1 hour before and 24 and 48 hours after challenge. Cell number values are given as means ± SEM. *P < .05 with respect to vehicle-treated animals; #P < .05 with respect to budesonide-treated rats (n = 5 to 8/group). Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 8 Mechanism by which proteasome inhibitors and corticosteroids could interact in a cell to elicit their anti-inflammatory activity. The illustration shows that, once activated, IκB is phosphorylated and then ubiquitinated before its degradation by the proteasome. This process then releases NF-κB, which translocates to the nucleus and binds to sites that initiate the transcription of IκB along with the induction of many proinflammatory molecules. This new IκB can then move into the cytoplasm to sequester free NF-κB, thereby resetting the inflammatory switch. PS-519 blocks the degradation of IκB at the level of the proteasome and hence inhibits activation of NF-κB and elicits its anti-inflammatory action. In addition, corticosteroids, such as budesonide, can bind to cytoplasmic steroid receptors, which move to the nucleus and bind to glucocorticosteroid response elements (GRE) . Activation of GRE leads to the transcription of IκB. Journal of Allergy and Clinical Immunology 1999 104, 294-300DOI: (10.1016/S0091-6749(99)70369-6) Copyright © 1999 Mosby, Inc. Terms and Conditions