Figure 7. Proposed regulatory pathways for Blimp1 and let-7c in dendritic cells.

A negative feedback loop between Blimp1 and let-7c regulates levels of SOCS1 and IL-6, and may explain the function of Blimp1 risk alleles. The effects of Blimp1 KO and/or siRNA knockdown (see experiments in Figure 1) remove inhibition of let-7c, thus leading to reduced SOCS1 expression (see experiments in Figure 3). Conversely, overexpression of Blimp1 leads to reduced let-7c expression and reduced IL-6 expression, either through enhanced SOCS1 expression or through direct effects of Blimp1 on IL-6 (data in Figure 4). Finally, transfection of let-7c reduces SOCS1 expression, and leads to increased expression of IL-6 (see data in Figure 5). These relationships are consistent with data from human cells (see Figure 6), which also relate lower Blimp1 levels to increased HLA-DR expression, possibly through release of inhibition of the CIITA transcription factor.