Fc gamma RIII-mediated production of TNF-alpha induces immune complex alveolitis independently of CXC chemokine generation.
We recently demonstrated a codominant role of C5aR and FcgammaRIII in the initiation of IgG immune complex-mediated inflammation in mice. In this study, we investigated the relative contribution of FcgammaRIII in the generation of several cytokines during experimental hypersensitivity pneumonitis/alveolitis in vivo. Induction of immune complex-alveolitis in C57BL/6 mice resulted in strong accumulation of neutrophils into the lung and enhanced chemotactic activity within bronchoalveolar lavage fluid accompanied by an increased production of the proinflammatory cytokines TNF-alpha and IL-1beta as well as the ELR-CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC). FcgammaRIII-deficient C57BL/6 mice (FcgammaRIII(-/-)) showed a marked reduction of the inflammatory response due to decreased production of TNF-alpha, IL-1beta, and MIP-2. Results obtained in C57BL/6 mice either lacking the TNF-alpha class I receptor (TNF-alphaRI(-/-)) or treated with neutralizing anti-TNF-alpha mAb demonstrated an essential contribution of TNF-alpha for mediating IL-1beta release, neutrophil influx, and hemorrhage. Surprisingly, MIP-2 and KC chemokine levels remained largely unaffected in TNF-alphaRI(-/-) mice or after functional inhibition of TNF-alpha. These data suggest that in immune complex alveolitis, the activation of FcgammaRIII may induce divergent downstream effector pathways with TNF-alpha acting independently of CXC chemokines to trigger the inflammatory response in C57BL/6 mice.
Chouchakova
N
N
Departments of. Clinical Immunology and Functional Anatomy, Medical School Hannover, Hannover, Germany.
Skokowa
J
J
Baumann
U
U
Tschernig
T
T
Philippens
K M
KM
Nieswandt
B
B
Schmidt
R E
RE
Gessner
J E
JE
D000542:Alveolitis, Extrinsic Allergic / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000936:Antigen-Antibody Complex / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D007105:Immune Complex Diseases / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000008:administration & dosage; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D007442:Intubation, Intratracheal; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology
D000936:Antigen-Antibody Complex; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D007375:Interleukin-1; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin