TLR4 is a negative regulator in noninfectious lung inflammation.
Low m.w. hyaluronan (LMW HA) has been shown to elicit the expression of proinflammatory cytokines and chemokines in various cells in vitro. However, the effects of this molecule in vivo are unknown. In this study, we report that intratracheal administration of LMW HA (200 kDa) causes inflammation in mouse lung. A lack of TLR4 is associated with even stronger inflammatory response in the lung as shown by increased neutrophil counts and elevated cytokine and chemokine concentrations. We also demonstrate that TLR4 anti-inflammatory signaling is dependent upon a MyD88-independent pathway. TLR4-mediated IL-1R antagonist production plays a negative regulatory role in LMW HA (200 kDa) induced lung inflammation. These data provide a molecular level explanation for the function of TLR4 in LMW HA (200 kDa)-induced lung inflammation, as inhibition of the beta form of pro-IL-1 promotes an anti-inflammatory response.
Zhao
Hang
H
Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. hzhao5@partners.org
Leu
Shaw-Wei
SW
Shi
Liyun
L
Dedaj
Rejmon
R
Zhao
Gaofeng
G
Garg
Hari G
HG
Shen
Lianjun
L
Lien
Egil
E
Fitzgerald
Katherine A
KA
Shiedlin
Aviva
A
Shen
Huahao
H
Quinn
Deborah A
DA
Hales
Charles A
CA
D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002463:Cell Membrane Permeability / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid