Mycobacterial and schistosomal antigen-elicited granuloma formation in IFN-gamma and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks.
Type 1 (IFN-gamma/TNF-dominant) and 2 (IL-4/IL-5-dominant) granulomatous inflammation were analyzed in mice with knockout of IFN-gamma or IL-4 genes. Lung granulomas were elicited by beads coated with purified protein derivative (PPD) of Mycobacteria bovis or soluble Schistosoma mansoni egg Ags. Parameters included granuloma size, composition, and macrophage function; white blood cell differentials; lymph node cytokine profiles; and cytokine/chemokine mRNA expression by lungs. Type 1 (PPD) and 2 (soluble Schistosoma mansoni egg Ags) responses showed characteristic cytokine and chemokine profiles in control mice. IFN-gamma knockout converted the PPD response to a type 2-like pattern with eosinophil infiltration and decreased TNF and RANTES, but increased IL-4, IL-5, IL-10, IL-13, monocyte chemoattractant protein-3 (MCP-3), and eotaxin expression. IL-4 knockout exacerbated type 1 inflammation with increased IL-2/IFN-gamma production by lymph nodes and IL-1 production by granuloma macrophages, but unexpectedly, IFN-gamma transcripts were reduced in lungs. Regarding the type 2 response, IL-4 was needed for maximal blood eosinophilia, but surprisingly, its absence had a minimal effect on type 2 granuloma size and composition despite regional reductions of IL-5 and IL-10 as well as local reductions of TNF-alpha, MCP-1, MCP-3, and eotaxin. Thus, the type 2 granuloma was not converted to a type 1 composition with IL-4 knockout, but showed persistent expression of IL-13 and some degree of IL-5 and MCP-3, suggesting that these cytokines could potentially support a compensatory type 2 response. IFN-gamma knockout did not augment type 2 granuloma size or Th2 cytokines in lymph nodes and unexpectedly reduced IL-4 transcripts in lungs. This study offers important implications regarding inflammation and its relationship to local and regional cytokine expression.
Chensue
S W
SW
Department of Pathology, Veterans Affairs Medical Center, University of Michigan, Ann Arbor 48105, USA. schensue@umich.edu
Warmington
K
K
Ruth
J H
JH
Lukacs
N
N
Kunkel
S L
SL
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D005260:Female; D006099:Granuloma / Q000145:classification / Q000209:etiology* / Q000276:immunology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics*; D007375:Interleukin-1 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012550:Schistosoma mansoni / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000942:Antigens, Bacterial; D000947:Antigens, Helminth; D018925:Chemokines; D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma