Neutralization of both IL-1α/IL-1β plays a major role in suppressing combined cigarette smoke/virus-induced pulmonary inflammation in mice.
Smoking is an important risk factor for the development of chronic obstructive pulmonary disease (COPD) and viral infections are believed to be major triggers of exacerbations, which periodically lead to a worsening of symptoms. The pro-inflammatory IL-1 family members IL-1α and IL-1β are increased in COPD patients and might contribute to disease pathology. We investigated whether individual or combined inhibition of these cytokines reduced lung inflammation in cigarette smoke (CS)-exposed and H1N1-infected BALB/c mice. Animals were treated with individual or combined antibodies (Abs) directed against IL-1α, IL-1β or IL-1R1. Cells in BAL fluid and cytokines/chemokines in lung homogenate were determined. The viral load was investigated. Blocking IL-1α had significant suppressive effects on total cells, neutrophils, and macrophages. Furthermore, it reduced KC levels significantly. Blocking of IL-1β did not provide significant activity. In primary human bronchial epithelial air-liquid-interface cell cultures infected with H1N1, IL-1α Abs but not IL-1β Abs reduced levels of TNF-α and IL-6. Concomitant usage of Abs against IL-1α/IL-1β revealed strong effects in vivo and reduced total cells, neutrophils and macrophages. Additionally, levels of KC, IL-6, TNF-α, MCP-1, MIP-1α and MIP-1β were significantly reduced and ICAM-1 and MUC5 A/C mRNA expression was attenuated. The viral load decreased significantly upon combined IL-1α/IL-1β Ab treatment. Blocking the IL-1R1 provided significant effects on total cells, neutrophils and macrophages but was inferior compared to inhibiting both its soluble ligands IL-1α/IL-1β. Our results suggest that combined inhibition of IL-1α/IL-1β might be beneficial to reduce CS/H1N1-induced airway inflammation. Moreover, combined targeting of both IL-1α/IL-1β might be more efficient compared to individual neutralization IL-1α or IL-1β or inhibition of the IL-1R1.
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Hannes
H
Bucher
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Samuel
S
Mang
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Martina
M
Keck
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Michèl
M
Przibilla
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
David J
DJ
Lamb
Immune-Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Felix
F
Schiele
Immune-Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Mareike
M
Wittenbrink
Immune-Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Klaus
K
Fuchs
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Birgit
B
Jung
Immune-Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany.
Klaus J
KJ
Erb
Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany. Electronic address: daniel.peter@boehringer-ingelheim.com.
Daniel
D
Peter
D000818:Animals; D000906:Antibodies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D053118:Influenza A Virus, H1N1 Subtype / Q000302:isolation & purification; D007251:Influenza, Human / Q000150:complications; D053582:Interleukin-1alpha / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000150:complications; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control*; D012307:Risk Factors; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha
COPD; Exacerbation; IL-1 pathway; Pulmonary inflammation; Treatment; Virus