Host resistance to mycobacteria is compromised by activation of the hypothalamic-pituitary-adrenal axis

Abstract

Host resistance to the growth of Mycobacterium avium and Mycobacterium tuberculosis is controlled by a gene, termed Nramp1, that maps to chromosome 1 in mice. Activation of the HPA axis or treatment of macrophages from susceptible mice with corticosterone suppresses the expression of Nramp1 mRNA and results in an increased susceptibility to mycobacterial growth. In contrast, neither activation of the HPA axis nor treatment of macrophages from resistant mice with corticosterone results in an alteration in their resistance or suppression of Nramp1 expression. Investigation into the mechanism of the differential response of the macrophages to corticosterone indicated that differences were associated with the stability of the mRNA in macrophages from BCG-resistant mice. Thus, corticosterone induced the accelerated degradation of Nramp1 mRNA as well as mRNA of several other macrophage activation genes in macrophages from BCG-susceptible mice. Treatment of macrophages with corticosterone before the induction of Nramp1 resulted in the accelerated degradation of mRNA in macrophages from both resistant and susceptible mice. The Nramp1 gene product appears to protect the mRNA of macrophage activation genes from degradation induced by corticosterone by an iron-dependent mechanism.