Chemokine expression dynamics in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation.

Transcript expression of 24 chemokines (CKs) was examined throughout 8 days in mouse lungs with type-1 (Th1) or type-2 (Th2) cytokine-mediated granulomas induced by bead-immobilized mycobacterial purified protein derivative or Schistosoma mansoni egg antigens. Where possible, CK protein levels were also measured. In addition, we examined effects of in vivo cytokine depletions. Findings were as follows: 1) bead challenge induced increases in 18 of 24 CK transcripts with type-1 and type-2 responses displaying different patterns. CKs fell into four categories: a) type-1-dominant (gamma-interferon-inducible protein (IP-10), monokine induced by INF-gamma (MIG), macrophage inflammatory protein-2 (MIP-2), lipopolysaccharide-induced chemokine (LIX), rodent growth-related oncogene homologue (KP), macrophage inflammatory protein-1alpha (MIP-1alpha) and -1beta (MIP-1beta), lymphotactin), b) type-2-dominant (eotaxin, monocyte chemotactic protein-2 (MCP-2) and -3 (MCP-3), liver and activation-regulated chemokine (LARC), T cell activation protein-3 (TCA-3), c) type-1 and type-2 co-dominant (MCP-1, MCP-5, monocyte-derived chemokine (MDC), thymus and activation-related chemokine (TARC), C10), and d) constitutive (lungkine, secondary lymphoid-tissue chemokine (SLC), EBI1-ligand chemokine (ELC), fractalkine, macrophage inflammatory protein-1gamma (MIP1-gamma), and stromal cell derived factor-1alpha (SDF1-alpha). 2) CKs displayed characteristic temporal patterns. CXC (IP-10, MIG, MIP-2, LIX, KC) and certain CC (MCP-1, MCP-5, MIP-1alpha, MIP-1beta) CKs were produced maximally within 1 to 2 days. Others (MCP-2, MCP-3, eotaxin, lymphotactin, LARC, TCA-3) displayed peak expression later. 3) Interferon-gamma neutralization profoundly abrogated MIG, but had little effect on other CKs. Tumor necrosis factor-alpha neutralization caused up to 50% reduction in a range of CKs. These findings indicate that type-1 and type-2 granulomas display characteristic CK profiles with coordinated expression that is under cytokine-mediated regulation.

IL-13 transgene state impairs mycobacterial (type-1) and schistosomal (type-2) antigen-elicited responses.

Transgenic technology provides one approach for examining cytokine properties in vivo. This study directly tested the effect of a lung-targeted IL-13 transgene on the induction and elicitation of Th1 and Th2 cell-mediated immuno-inflammatory responses. Induction of Th1 (type 1) and Th2 (type 2) responses were tested by sensitization of IL-13 transgenics and littermates with purified protein derivative (PPD) of Mycobacterium bovis or Schistosoma mansoni eggs. Secondary elicitation of pulmonary granulomas was examined in adoptively sensitized transgenics and littermates challenged with bead-bound PPD or S. mansoni egg antigens. Parameters included lymphoid tissue cytokine profiles and granuloma sizes. Results showed that induction and elicitation of both type 1 and type 2 cytokines and granulomas were significantly abrogated in transgenics. Systemic effects were possible, as transgenic serum contained high levels of circulating IL-13. These findings support the concept that IL-13 impairs effector functions and provide novel information regarding its role in regulating Th2 cytokines.