Regulation of T helper cell subsets by cyclooxygenases and their metabolites

Abstract

Cyclooxygenases and their metabolites are important regulators of inflammatory responses and play critical roles in regulating the differentiation of T helper cell subsets in inflammatory diseases. In this review, we highlight new information on regulation of T helper cell subsets by cyclooxygenases and their metabolites. Prostanoids influence cytokine production by both antigen presenting cells and T cells to regulate the differentiation of naïve CD4(+) T cells to Th1, Th2 and Th17 cell phenotypes. Cyclooxygenases and PGE2 generally exacerbate Th2 and Th17 phenotypes, while suppressing Th1 differentiation. Thus, cycloxygenases may play a critical role in diseases that involve immune cell dysfunction. Targeting of cyclooxygenases and their eicosanoid products may represent a new approach for treatment of inflammatory diseases, tumors and autoimmune disorders.

Figure 1

Arachidonic acid metabolism by COX-1 and COX-2. COX1 and COX-2 convert arachidonic acid to PGH2. PGH2 is a substrate for terminal synthases which generate PGE2, PGD2, PGF2α, PGI2 and TXA2, which activate cell signaling through their cognate receptors, EP1-4, DP1-2, FP, IP and TP.

Figure 2

Differentiation of Th cell subsets. Naïve CD4⁺ T cells are activated by antigen-presenting cells (APCs) in the presence of co-stimulation through CD28 and/or inducible T-cell co-stimulator (ICOS). The cytokine microenvironment determines the terminal lineage commitment and cytokine expression profiles. IL-12, through STAT4, potentiates the production of IFN-γ and the expression of the transcription factor T-bet. T-bet increases IFN-γ which maintains Th1-cell-lineage commitment. IL-4, activates STAT6 to increase expression of GATA3. GATA3 potentiates IL-4 and IL-13 expression, which determines Th2-cell-lineage differentiation. TGF-β and IL-6 function through STAT6 to increases the expression of RORγt and promote CD4⁺ T cells to Th17 effector cells that produce IL-17A and IL-17F. TGF-β can convert Th2 cells to Th9 cells that produce IL-9, IL-10 and IL-13 by increasing expression of PU.1 and IRF4 transcription factors. T-bet- T-box expressed in T cells; GATA3, GATA-binding protein 3; IFNγ, interferon-γ; RORγt-retinoic acid receptor-related orphan receptor-γt.

Figure 3

Regulation of Th1 differentiation and activation by PGE₂. Differentiation to Th1 vs. Th2 cells is controled by the balance of IL-12 and IL-4 cytokines. PGE₂ downregulates IL-12 production and Th1-inducing capacity of APCs. In the absence of IL-12 production, Th2 differentiation is enhanced. Th2 cells secrete IL-4 which augments Th2 cell development. Th2 cell-derived IL-4 also provides feedback inhibition on APCs to diminish COX-2 expression to restore Th1/Th2 balance.

Figure 4

Regulation of Th2 cell immune response by COXs and PGs. Th2 cell differentiation is regulated by COXs and PGs in the inflammatory cytokine microenvironment. (A) PGE₂ inhibits IL-12 production by DCs and macrophages, which reduces Th1 differentiation. PGE₂ inhibits IL-12 receptor expression and IFN-γ and IL-2 secretion by Th1 cells. (B) PGE₂ indirectly promotes Th2 differentiation and autocrine signaling through increased IL-4 in Th2 cells. (C) PGE₂, via EP2 and EP4 receptors, promotes COX-2 transcription in macrophages and DCs, resulting in a COX-2 positive feedback loop. (D) Increased IL-4 production in Th2 cells inhibits COX-2 expression in DCs and macrophages, which forms a negative feedback loop in Th2 cell immune response. (E) PGD₂ and PGI₂ directly promote Th2 cell immune response.

Figure 5

Regulation of Th17 cell differentiation by COX-2 and PGs. (A) Binding of PGE₂ to EP2 and EP4 on DCs leads to increased IL-23 and IL-1β expression. In addition, PGE₂ induces IL-23R and IL-1R expression on CD4⁺ T cells. The IL-23 and IL-1β signals activate Stat3 and upregulate RORγt, which in conjunction with TGF-β and IL-6, leads to IL-17 expression. (B) Autocrine effect of PGI₂ and PGF_2α on Th17 cell differentiation. CD4⁺ T cells generate PGI₂ and PGF_2α. Activation of IP and FP receptors on CD4⁺ T cells induces Stat3 signaling and upregulation of RORγt, which enhances TGF-β and IL-6 induction of IL-17 expression.