J. Neurochem. (2011) 116, 438–448.

Death‐inducing ligands tumor necrosis factor alpha (TNFα) and Fas ligand (FasL) do not kill cultured astrocytes; instead they induce a variety of chemokines including macrophage‐inflammatory protein‐1α/CC chemokine ligand 3 (CCL3), monocyte chemoattractant protein‐1 (CC CCL‐2), macrophage‐inflammatory protein‐2/CXC chemokine ligand 2 (CXCL2, a murine homologue of interleukin 8), and interferon‐induced protein of 10 kDa (CXCL10). Induction is enhanced by protein synthesis inhibition suggesting the existence of endogenous inhibitors. ERK, NF‐κB, heat shock factor‐1 (HSF‐1) and heat shock proteins were examined for their possible roles in signal transduction. Inhibition of ERK activation by PD98059 partially inhibited expression of all but FasL‐induced CXCL10. Although inhibition of NF‐κB DNA binding inhibited chemokine induction, PD98059 did not inhibit TNFα‐induced NF‐κB DNA binding suggesting that ERK serves an NF‐κB‐independent pathway. Heat shock itself induced astrocytic chemokine expression; both TNFα and FasL induced HSF‐1 DNA binding and Hsp72 production; and Hsp72‐induced chemokine expression. Inhibition of either HSF‐1 binding with quercetin or heat shock protein synthesis with KNK437 compromised chemokine induction without compromising cell survival. These data suggest that the induction of heat shock proteins via HSF‐1 contribute to the TNFα‐ and FasL‐induced expression of chemokines in astrocytes.