title: Proinflammatory cytokine surge after injury stimulates an airway immunoglobulin a increase.
abstract: BACKGROUND
  : Injury stimulates an innate airway IgA response in severely injured patients, which also occurs in mice. Tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate the production of polymeric immunoglobulin receptor, the protein required to transport immunoglobulin A (IgA) to mucosal surfaces. Blockade of TNF-α and IL-1β eliminates the airway IgA response to injury. IL-6 stimulates differentiation of B cells into IgA-secreting plasma cells at mucosal sites. We investigated the local and systemic kinetics of TNF-α, IL-1β, and IL-6 after injury in mice. We also hypothesized that injection of exogenous TNF-α, IL-1β, and IL-6 would replicate the airway IgA response to injury.
  
  
  METHODS
  : Experiment 1: male Institute of Cancer Research mice were randomized to uninjured controls (n = 8) or to surgical stress with laparotomy and neck incisions, with killing at 1, 2, 3, 5, or 8 hours after injury (n = 8/group). Bronchoalveolar lavage (BAL) and serum levels of TNF-α, IL-1β, and IL-6 were analyzed by enzyme-linked immunosorbent assay. Experiment 2: male Institute of Cancer Research mice were randomized to uninjured controls (n = 6), injury (surgical stress that was similar to experiment 1 except the peritoneum was left intact, n = 6), or cytokine injection with intraperitoneal injection of recombinant TNF-α, IL-1β, and IL-6. Animals were killed at 2 hours after injury, and nasal airway lavage and BAL IgA were analyzed by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  : Experiment 1: BAL TNF-α, IL-1β, and IL-6 levels increased in bimodal pattern after injury at 3 hours and 8 hours versus controls (p < 0.05). Serum IL-6 did not increase at 3 hours, but did show a significant increase by 5 hours versus control (p < 0.05). Serum levels of TNF-α and IL-1β did not change. Experiment 2: both Injury and combination TNF-α, IL-1β, and IL-6 cytokine injection significantly increased IgA levels in airway lavage (BAL + nasal airway lavage) compared with control (p < 0.01 for both).
  
  
  CONCLUSIONS
  : Airway levels of TNF-α, IL-1β, and IL-6 increase in a bimodal pattern after injury with peaks at 3 hours and 8 hours, which do not correspond to serum changes. The peak at 8 hours is consistent with the known increase in airway IgA after injury. Intraperitoneal injection of a combination exogenous TNF-α, IL-1β, and IL-6 replicates the airway IgA increase after injury. This effect is not seen with individual cytokine injections.
authors.affiliation: Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jonker
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sano
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Hermsen
authors.forename: Jinggang
authors.initials: J
authors.lastname: Lan
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kudsk
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D018928:Immunity, Mucosal / Q000276:immunology*; D007070:Immunoglobulin A / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007421:Intestine, Small / Q000293:injuries*; D008297:Male; D051379:Mice; D010865:Pilot Projects; D053717:Pneumonia, Ventilator-Associated / Q000276:immunology*; D019056:Receptors, Polymeric Immunoglobulin / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007070:Immunoglobulin A; D053583:Interleukin-1beta; D015850:Interleukin-6; D019056:Receptors, Polymeric Immunoglobulin; D014409:Tumor Necrosis Factor-alpha