Interleukin-12 can directly induce T-helper 1 responses in interferon-gamma (IFN-gamma) receptor-deficient mice, but requires IFN-gamma signalling to downregulate T-helper 2 responses

TY - JOUR

T1 - Interleukin-12 can directly induce T-helper 1 responses in interferon-gamma (IFN-gamma) receptor-deficient mice, but requires IFN-gamma signalling to downregulate T-helper 2 responses

AU - Mountford, A.P.

AU - Coulson, P.S.

AU - Wynn, T.A.

AU - Cheever, A.W.

AU - Sher, A.

AU - Wilson, R.A.

N1 - Open access copy available from the journal web site.

PY - 1999/8

Y1 - 1999/8

N2 - An in vivo model of pulmonary granuloma formation around embolized schistosome eggs was investigated as an environment in which to analyse a role for interleukin-12 (IL-12) in the differentiation of T-helper 1 (Th1) and Th2 subsets. Specifically, mice deficient for the interferon-¿ receptor (IFN-¿R-/–) were used to determine the role for IL-12 in the absence of IFN-¿-mediated signalling. We show that recombinant IL-12 administered to IFN-¿R-/– mice caused the up-regulation of mRNA for IFN-¿ in lung tissue, and the secretion of abundant IFN-¿ by in vitro-cultured lymph node cells in response to egg antigens. This indicates that IL-12 can act independently of IFN-¿ to induce the development of Th1 cells. Administration of rIL-12 to wild-type mice markedly reduced the secretion of Th2-associated cytokines, IL-4 and IL-5. However, these cytokines were not dramatically reduced in IFN-¿R-/– mice treated with IL-12. We conclude that inhibition of these cytokines by IL-12 is primarily dependent upon effective IFN-¿ signalling, although abrogation of T-cell derived IL-10 appeared to be dependent upon IL-12. We also show that increases in mRNA for the ß2 subunit of the IL-12 receptor and the p40 subunit of IL-12 after rIL-12 treatment were lower in IFN-¿R-/– mice, compared to wild-type mice, indicating that their expression was primarily dependent upon IFN-¿ with only a minor role for IL-12.

AB - An in vivo model of pulmonary granuloma formation around embolized schistosome eggs was investigated as an environment in which to analyse a role for interleukin-12 (IL-12) in the differentiation of T-helper 1 (Th1) and Th2 subsets. Specifically, mice deficient for the interferon-¿ receptor (IFN-¿R-/–) were used to determine the role for IL-12 in the absence of IFN-¿-mediated signalling. We show that recombinant IL-12 administered to IFN-¿R-/– mice caused the up-regulation of mRNA for IFN-¿ in lung tissue, and the secretion of abundant IFN-¿ by in vitro-cultured lymph node cells in response to egg antigens. This indicates that IL-12 can act independently of IFN-¿ to induce the development of Th1 cells. Administration of rIL-12 to wild-type mice markedly reduced the secretion of Th2-associated cytokines, IL-4 and IL-5. However, these cytokines were not dramatically reduced in IFN-¿R-/– mice treated with IL-12. We conclude that inhibition of these cytokines by IL-12 is primarily dependent upon effective IFN-¿ signalling, although abrogation of T-cell derived IL-10 appeared to be dependent upon IL-12. We also show that increases in mRNA for the ß2 subunit of the IL-12 receptor and the p40 subunit of IL-12 after rIL-12 treatment were lower in IFN-¿R-/– mice, compared to wild-type mice, indicating that their expression was primarily dependent upon IFN-¿ with only a minor role for IL-12.

KW - MURINE SCHISTOSOMIASIS-MANSONI

KW - CELL STIMULATORY FACTOR

KW - GRANULOMA-FORMATION

KW - IMMUNOREGULATORY FUNCTIONS

KW - PROINFLAMMATORY CYTOKINE

KW - IMMUNE-RESPONSES

KW - LEISHMANIA-MAJOR

KW - TH1 DEVELOPMENT

KW - IN-VIVO

KW - IL-12

U2 - 10.1046/j.1365-2567.1999.00832.x

DO - 10.1046/j.1365-2567.1999.00832.x

M3 - Article

VL - 97

SP - 588

EP - 594

JO - Immunology

JF - Immunology

SN - 0019-2805

IS - 4

ER -