The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD.

Abstract

BACKGROUND:

Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids.

METHODS:

Pgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry.

RESULTS:

There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all).

CONCLUSIONS:

Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity.

• Authors: Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N Reynolds, Sandra Hodge
• Journal: Respiratory research (Respir Res) Vol. 14 Pg. 63 (Jun 03 2013) ISSN: 1465-993X [Electronic] England
• PMID: 23731729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anti-Inflammatory Agents
• Cytokines
• Cyclosporine
• Granzymes
• Methylprednisolone

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, drug effects)
• Aged
• Anti-Inflammatory Agents (therapeutic use)
• Cyclosporine (therapeutic use)
• Cytokines (biosynthesis)
• Female
• Granzymes (biosynthesis)
• Humans
• Inflammation (drug therapy, etiology)
• Leukocyte Count
• Lymphocytes (drug effects)
• Male
• Methylprednisolone (therapeutic use)
• Middle Aged
• Pulmonary Disease, Chronic Obstructive (complications, drug therapy)
• T-Lymphocytes, Cytotoxic (drug effects)