IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor beta 1

• Published in: The Journal of immunology (1950) Vol. 171; no. 12; pp. 6866 - 6874
• Main Authors: Russell, Tonya D, Yan, Qingyun, Fan, Guangshun, Khalifah, Anthony P, Bishop, D Keith, Brody, Steven L, Walter, Michael J
• Format: Journal Article
• Language: English
• Published: United States 15.12.2003
• Subjects: Animals; Antigens, CD - chemistry; Antigens, CD - physiology; Chemotactic Factors - chemistry; Chemotactic Factors - physiology; Chemotaxis - immunology; Cytoplasm - chemistry; Cytoplasm - genetics; Dimerization; Down-Regulation - genetics; Down-Regulation - immunology; Interleukin-12 - chemistry; Interleukin-12 - physiology; Interleukin-12 Subunit p40; Macrophages, Alveolar - immunology; Macrophages, Alveolar - pathology; Macrophages, Alveolar - virology; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NIH 3T3 Cells; Protein Subunits - chemistry; Protein Subunits - physiology; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - deficiency; Receptors, Interleukin - genetics; Receptors, Interleukin - physiology; Receptors, Interleukin-12; Receptors, Tumor Necrosis Factor - chemistry; Receptors, Tumor Necrosis Factor - physiology; Receptors, Tumor Necrosis Factor, Type II; Respiratory Tract Infections - genetics; Respiratory Tract Infections - immunology; Respiratory Tract Infections - pathology; Respirovirus Infections - genetics; Respirovirus Infections - immunology; Respirovirus Infections - pathology; Sendai virus - immunology; Sequence Deletion
• ISSN: 0022-1767
• DOI: 10.4049/jimmunol.171.12.6866

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.