IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor beta 1.
Leukocyte recruitment to the airway lumen is a central feature of inflammatory conditions such as asthma and respiratory viral infection. Characterization of mediators that regulate leukocyte recruitment in these conditions revealed increased IL-12 p40 homodimer (p80) levels were associated with enhanced airway macrophage accumulation. To examine this association, we used in vivo and in vitro assays to demonstrate p80, but not IL-12 or p40, provided a macrophage chemoattractant signal. Macrophages from genetically deficient mice indicated p80-dependent chemotaxis was independent of IL-12 and required IL-12Rbeta1 (Rbeta1) expression. Furthermore, analysis of murine cell lines and primary culture macrophages revealed Rbeta1 expression, with an intact cytoplasmic tail, was necessary and sufficient to mediate p80-dependent chemotaxis. To examine the role for Rbeta1 in mediating macrophage accumulation in vivo, we contrasted Sendai virus-driven airway inflammation in wild-type and Rbeta1-deficient mice. Despite similar viral burden and production of the macrophage chemoattractant p80, the Rbeta1-deficient mice displayed a selective decrease in airway macrophage accumulation and resistance to viral-dependent mortality. Thus, Rbeta1 mediates p80-dependent macrophage chemotaxis and inhibition of the p80-Rbeta1 interaction may provide a novel anti-inflammatory strategy to manipulate the inflammation associated with asthma and respiratory viral infection.
Russell
Tonya D
TD
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Yan
Qingyun
Q
Fan
Guangshun
G
Khalifah
Anthony P
AP
Bishop
D Keith
DK
Brody
Steven L
SL
Walter
Michael J
MJ
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology; D002630:Chemotactic Factors / Q000737:chemistry / Q000502:physiology; D002633:Chemotaxis / Q000276:immunology*; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics; D019281:Dimerization; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000737:chemistry / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology / Q000821:virology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053707:Receptors, Interleukin-12; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D012141:Respiratory Tract Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010253:Respirovirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D029082:Sendai virus / Q000276:immunology; D017384:Sequence Deletion
D015703:Antigens, CD; D002630:Chemotactic Factors; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D018664:Interleukin-12