Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN-gamma over IL-4 responses.
Human interferon-inducible protein 10 (IP-10) differs from most chemokines in its apparent specificity for activated T lymphocytes. We hypothesized that IP-10 was relevant not only for recruiting T cells to inflammatory sites, but also for regulating cytokine synthesis patterns. We examined the effect of recombinant human IP-10 (rhIP-10) on human interferon gamma (IFN-gamma) and interleukin 4 (IL-4) production by fresh peripheral blood mononuclear cells. We demonstrate for the first time that this CXC chemokine selectively up-regulates human T cell cytokine synthesis, with enhancement selectively targeted to promotion of Th1-like dominance. Superantigen (TSST-1), soluble anti-CD3 mAb, and phytohemagglutinin were used to activate distinct intracellular signaling pathways, thereby inducing quantitatively different IFN-gamma:IL-4 ratios. Selective enhancement of IFN-gamma responses was consistently observed, with median increases of 105-470%. Environmental antigens (Ag) were used to evaluate IP-10's effect on CD4-dependent, chloroquine-sensitive cytokine synthesis. Ag-driven IFN-gamma responses exhibited median 19- to 30-fold increases in the presence of nanomolar concentrations of rhIP-10. IL-4 responses were neither enhanced nor inhibited under any of the conditions tested. These findings suggest a potential role for this T cell-focused chemokine in maintenance of the default Th1-like responses usually seen to environmental Ag and indicate a potential application in the modulation of Ag-driven responses in vivo.
Gangur
V
V
Department of Immunology, The University of Manitoba, Winnipeg, Canada.
Simons
F E
FE
Hayglass
K T
KT
D000293:Adolescent; D000328:Adult; D000941:Antigens; D002455:Cell Division / Q000187:drug effects; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008875:Middle Aged; D008934:Mitogens; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D018417:Th1 Cells; D018418:Th2 Cells
D000941:Antigens; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D007376:Interleukin-2; D008934:Mitogens; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma