title: Mucosal IL-12 is more effective than systemic IL-12 in augmenting IFN-gamma expression and inhibiting allergic lung eosinophilia in murine lungs.
abstract: The relative efficacy of mucosal (intratracheal) and systemic (intraperitoneal) delivery of interleukin (IL)-12 was evaluated in a mouse model of allergic lung eosinophilia. Mucosal administration of IL-12 achieved 100- to 600-fold higher bronchoalveolar lavage (BAL) levels of IL-12, but 2- to 10-fold lower serum levels compared to systemic administration. Whereas both mucosal and systemic IL-12 inhibited BAL eosinophil recruitment at high doses (100-1000 ng), only mucosal IL-12 was effective at low doses (1-10 ng). Mucosal, but not systemic, administration of 1000 ng of IL-12 increased interferon (IFN)-gamma expression in BAL cells. In a model of ongoing eosinophilic inflammation, when mucosal or systemic IL-12 doses were initiated prior to peak eosinophilia, further eosinophil recruitment was inhibited. However, when IL-12 treatment was initiated after peak eosinophil recruitment occurred, recovery from eosinophilic inflammation was not facilitated. Our findings are the first to demonstrate that locally administered IL-12 inhibits eosinophil recruitment at 100-fold lower doses than systemic IL-12. The most likely mechanism of this enhanced inhibitory activity is a sustained increase in lung levels of IL-12 that augments IFN-gamma production from BAL cells. We suggest that future studies should evaluate the efficacy of low doses of nebulized IL-12 in inhibiting eosinophilic lung inflammation in asthma.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555-0762, USA. Sasur@utmb.edu
authors.forename: S
authors.initials: S
authors.lastname: Sur
authors.forename: B K
authors.initials: BK
authors.lastname: Choudhury
authors.forename: J S
authors.initials: JS
authors.lastname: Lam
authors.forename: P
authors.initials: P
authors.lastname: Bouchard
authors.forename: J S
authors.initials: JS
authors.lastname: Wild
authors.forename: N
authors.initials: N
authors.lastname: Sur
authors.forename: R
authors.initials: R
authors.lastname: Alam
authors.forename: A
authors.initials: A
authors.lastname: Sigounas
authors.forename: D
authors.initials: D
authors.lastname: Holbert
authors.forename: M R
authors.initials: MR
authors.lastname: Van Scott
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000097:blood; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000097:blood; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011058:Pollen / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma