Regulation and Phenotype of an Innate Th1 Cell: Role of Cytokines and the p38 Kinase Pathway

Abstract

We have explored the phenotype and regulation of Th1 cell activation by the cytokines IL-12 and IL-18. We demonstrate that these two cytokines selectively induce IFN-γ in a differentiated Th1 cell population through the previously described p38 mitogen-activated protein (MAP) kinase pathway. Using a highly selective p38 MAP kinase inhibitor, we demonstrate that it is possible to block IFN-γ induction from activated, differentiated Th1 cells via p38 MAP kinase without disrupting the activation and differentiation of naive T cells or the proliferation of naive or differentiated T cells. In addition, IL-12 and IL-18 provide an Ag and IL-2-independent survival signal to this uniquely differentiated Th1 cell population. We hypothesize that this Ag-independent survival of Th1 cells may participate in an innate inflammatory loop with monocytes at the sites of chronic inflammation. In addition, p38 MAP kinase inhibition of this cytokine-regulated pathway may be a unique mechanism to inhibit chronic inflammation without disruption of Ag-driven activation and function of naive T cells.

IL-18 Bridges Innate and Adaptive Immunity through IFN-γ and the CD134 Pathway

“…Interestingly, IL-18 directly induces division and cytokine secretion by effector or memory T cells in the absence of recall Ag (29,58). However, naive T cells do not express the IL-18R (27), and therefore it was surprising that IL-18 boosted the CD4 T cells in our model.…”

Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation

“…However, the role of p38 in polarization of Th1 cells is not as clear. Although the p38 inhibitors SB203580 and SC-409 blocked cytokine-mediated IFN-␥ production by Th1 cells, they did not prevent the activation, differentiation, or proliferation of new Th1 cells (5). Recently generated p38␣ Ϫ/Ϫ T and B cells developed and proliferated normally (7), and p38␣-deficient CD4 ϩ T cells differentiated into Th1 effector cells in vitro and expressed normal levels of IFN-␥ when restimulated through the TCR (8), suggesting that T cell p38␣ is dispensable for Th1 development.…”

“…Recently, however, p38␣ Ϫ/Ϫ T and B cells were found to develop normally (7), and p38␣-deficient CD4 ϩ T cells expressed normal levels of IFN-␥ when differentiated in vitro under Th1-polarizing conditions (8). It was also reported that p38 inhibitors blocked cytokine-induced Th1 IFN-␥ production without disrupting the activation and differentiation of new Th1 effector (5). Hence, there is good evidence of the importance of p38 in Th1 IFN-␥ production, but the role of p38 in Th1 cell differentiation needs to be clarified.…”

“…However, the role of p38 in Th1 development is not entirely clear. In vitro polarized Th1 cells expressing constitutively active MAP kinase kinase (MKK) 6, an upstream activator of p38, displayed increased IFN-␥ production, whereas expression of a dominant negative form of p38 or treatment with the p38 inhibitor SB203580 decreased IFN-␥ expression by Th1 effectors (4,5). Recently, however, p38␣ Ϫ/Ϫ T and B cells were found to develop normally (7), and p38␣-deficient CD4 ϩ T cells expressed normal levels of IFN-␥ when differentiated in vitro under Th1-polarizing conditions (8).…”

Interleukin-18 genetics and inflammatory disease susceptibility

“…13 On binding of IL-18 to IL-18Ra, IL-18Rb is recruited and induces signalling pathways common to other IL-1R family members such as myeloid differentiation 88 (MyD88), IL-1R-associated kinase (IRAK), tumour necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor kB (NF-kB), and other downstream effectors. [14][15][16][17][18][19] IL-18 also has a soluble decoy receptor/inhibitor -IL-18-binding protein (IL-18BP). IL-18BP binds to IL-18 preventing it from associating with IL-18R and therefore inhibiting IL-18-induced IFN-g production.…”