Involvement of Na⁺/H⁺ exchangers in induction of cyclooxygenase-2 by vacuolar-type (H⁺)-ATPase inhibitors in RAW 264 cells

In the mouse macrophage-like cell line RAW 264, vacuolar-type (H⁺)-ATPase (V-ATPase) inhibitors, bafilomycin A₁ and concanamycin A, increased the level of cyclooxygenase (COX)-2 protein and its mRNA. The V-ATPase inhibitor-induced expression of COX-2 was suppressed by inhibitors of c-jun N-terminal kinase (JNK) and nuclear factor-κB, and by inhibitors of Na⁺/H⁺ exchangers (NHEs). The bafilomycin A₁-induced activation of JNK but not degradation of IκB-α was suppressed by NHE inhibitors and by an inhibitor of Na⁺/Ca²⁺ exchanger SN-6. These results suggested that V-ATPase inhibitors induce the expression of COX-2 via NHE-dependent and -independent pathways.