RelB modulation of I kappa B alpha stability as a mechanism of transcription suppression of interleukin-1 alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor alpha in fibroblasts

Members of the NF-kappa B/RelB family of transcription factors play importa nt roles in the regulation of inflammatory and immune responses. RelB, a me mber of this family, has been characterized as a transcription activator an d is involved in the constitutive NF-kappa B activity in lymphoid tissues. However, in a previous study me observed an overexpression of chemokines in RelB-deficient fibroblasts. Here me show that RelB is an important transcr iption suppressor in fibroblasts which limits the expression of proinflamma tory mediators and may exert its function by modulating the stability of I kappa B alpha protein. Fibroblasts from relb(-/-) mice overexpress interleu kin-1 alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor alpha in res ponse to lipopolysaccharide (LPS) stimulation, These cells have an augmente d and prolonged LPS-inducible IKK activity and an accelerated degradation w hich results in a diminished level of I kappa B alpha protein, despite an u pregulated I kappa B alpha mRNA expression. Consequently, NF-kappa B activi ty was augmented and postinduction repression of NF-kappa B activity was im paired in these cells.. The increased kappa B-binding activity and cytokine overexpression was suppressed by introducing RelB cDNA or a dominant negat ive I kappa B alpha into relb(-/-) fibroblasts. Our findings suggest a nove l transcription suppression function of RelB in fibroblasts.