Pulmonary Expression of Leukemia Inhibitory Factor Induces B Cell Hyperplasia and Confers Protection in Hyperoxia*

Leukemia inhibitory factor (LIF) is produced by a large number of pulmonary cells in response to diverse stimuli. Exaggerated levels of LIF have also been detected in the adult respiratory distress syndrome and other disorders. The biologic effects of LIF in the lung, however, have not been elucidated. To define the respiratory effects of LIF, we generated transgenic mice in which human LIF was selectively targeted to the mature lung. In these mice, transgene activation caused an impressive increase in bronchoalveolar lavage (BAL) cellularity with a significant increase in BAL and tissue B lymphocytes. LIF also conferred protection in 100% O2 where it decreased alveolar-capillary protein leak and enhanced survival. This protective effect was associated with the induction of interleukin (IL)-6 mRNA and protein. LIF transgenic mice with a null mutation in IL-6 were more sensitive to the toxic effects of 100% O2 than LIF-transgenic animals with a wild-type IL-6 locus. These studies demonstrate that LIF induces B cell hyperplasia and confers protection in hyperoxic acute lung injury. They also demonstrate that LIF induces IL-6 and that the protective effects of LIF are mediated, in part, via this inductive event. LIF may be an important regulator of B cell-mediated responses and oxidant injury in the lung.

[1]  P. Waring,et al.  Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids. , 1992, The Journal of clinical investigation.

[2]  L. Smith.  Hyperoxic lung injury: biochemical, cellular, and morphologic characterization in the mouse. , 1985, The Journal of laboratory and clinical medicine.

[3]  I. Otterness,et al.  Neutralization of endogenous IL-6 suppresses induction of IL-1 receptor antagonist. , 1995, Journal of immunology.

[4]  R. Homer,et al.  Interferon γ Induction of Pulmonary Emphysema in the Adult Murine Lung , 2000, The Journal of experimental medicine.

[5]  S. Korsching,et al.  Tissue-specific and ontogenetic regulation of LIF protein levels determined by quantitative enzyme immunoassay. , 1997, Growth factors.

[6]  P. Waring,et al.  Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Wiggs,et al.  Localization of leukaemia inhibitory factor to airway epithelium and its amplification of contractile responses to tachykinins , 1997, British journal of pharmacology.

[8]  J. Aubin,et al.  Biphasic effects of leukemia inhibitory factor on osteoblastic differentiation * , 2001, Journal of cellular biochemistry. Supplement.

[9]  J. Shelhamer,et al.  Leukemia inhibitory factor induces the 85-kDa cytosolic phospholipase A2 gene expression in cultured human bronchial epithelial cells. , 1997, Biochimica et biophysica acta.

[10]  R. Homer,et al.  Interleukin-6-induced protection in hyperoxic acute lung injury. , 2000, American journal of respiratory cell and molecular biology.

[11]  Y. Nagai,et al.  The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation. , 1995, British journal of rheumatology.

[12]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[13]  O. Kozawa,et al.  Leukemia inhibitory factor enhances bFGF-induced IL-6 synthesis in osteoblasts: involvement of JAK2/STAT3. , 2002, Cellular signalling.

[14]  L. Bossaert,et al.  High levels of leukaemia inhibitory factor in ARDS. , 1996, Cytokine.

[15]  R. Homer,et al.  Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. , 1999, The Journal of clinical investigation.

[16]  B. Stripp,et al.  Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. , 1994, The Journal of clinical investigation.

[17]  A. Munafo,et al.  Leukemia inhibitory factor in human reproduction. , 2001, Fertility and sterility.

[18]  R. Flavell,et al.  Airway hyperresponsiveness and airway obstruction in transgenic mice. Morphologic correlates in mice overexpressing interleukin (IL)-11 and IL-6 in the lung. , 2000, American journal of respiratory cell and molecular biology.

[19]  R. Homer,et al.  Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. , 1998, The Journal of clinical investigation.

[20]  D. Knight,et al.  Leukemia inhibitory factor (LIF) and LIF receptor in human lung. Distribution and regulation of LIF release. , 1999, American journal of respiratory cell and molecular biology.

[21]  R. Flavell,et al.  Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction. , 1996, The Journal of clinical investigation.

[22]  C. Ware,et al.  Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. , 1995, Development.

[23]  M. Azari,et al.  Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis , 2001, Brain Research.

[24]  R. Flavell,et al.  Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes. , 1997, The Journal of clinical investigation.

[25]  M. Brown,et al.  Leukaemia inhibitory factor and interleukin 6 are expressed at very low levels in the normal adult mouse and are induced by inflammation. , 1994, Cytokine.

[26]  J. Crapo.  Morphologic changes in pulmonary oxygen toxicity. , 1986, Annual review of physiology.

[27]  J. Hogg,et al.  Particulate matter induces cytokine expression in human bronchial epithelial cells. , 2001, American journal of respiratory cell and molecular biology.

[28]  Y. Donati,et al.  Oxygen toxicity in mouse lung: pathways to cell death. , 1998, American journal of respiratory cell and molecular biology.

[29]  M. Ogawa,et al.  Human carcinoma cell lines produce biologically active leukemia inhibitory factor (LIF). , 1994, Research communications in molecular pathology and pharmacology.

[30]  D. Knight.  Leukaemia inhibitory factor (LIF): a cytokine of emerging importance in chronic airway inflammation. , 2001, Pulmonary pharmacology & therapeutics.

[31]  H. Tilg,et al.  Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. , 1994, Blood.

[32]  H. Yoon,et al.  Rhinovirus regulation of IL-1 receptor antagonist in vivo and in vitro: a potential mechanism of symptom resolution. , 1999, Journal of immunology.

[33]  F. Gao,et al.  Regulation of cardiac fibroblast cellular function by leukemia inhibitory factor. , 2002, Journal of molecular and cellular cardiology.