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) granulomato us 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 cytoki ne profiles; and cytokine/chemokine mRNA expression by lungs. Type 1 ( PPD) and 2 (soluble Schistosoma mansoni egg Ags) responses showed char acteristic cytokine and chemokine profiles in control mice. IFN-gamma knockout converted the PPD response to a type 2-like pattern with eosi nophil infiltration and decreased TNF and RANTES, but increased IL-4, IL-5, IL-10, IL-13, monocyte chemoattractant protein-3 (MCP-3), and eo taxin expression. IL-4 knockout exacerbated type 1 inflammation with i ncreased IL-2/IFN-gamma production by lymph nodes and IL-l 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 minima l effect on type 2 granuloma size and composition despite regional red uctions of IL-5 and IL-10 as well as local reductions of TNF-alpha, MC P-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 expr ession of IL-13 and some degree of IL-5 and MCP-3, suggesting that the se cytokines could potentially support a compensatory type 2 response. IFN-gamma knockout did not augment type 2 granuloma size or Th2 cytok ines 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.