Prolonged activation of jun and collagenase genes by tumour necrosis factor-α

Abstract

Tumour necrosis factor-alpha (TNF-alpha) is secreted by macrophages in response to inflammation, infection and cancer. Sublethal doses of recombinant TNF-alpha to rats causes cachexia, anaemia and inflammation. TNF-alpha plays a major part in tissue inflammation and remodelling by stimulating production of collagenase. Cellular responses to TNF-alpha are initiated by binding to high-affinity cell surface receptors. TNF-alpha then profoundly affects gene regulation, stimulating the fos, myc, interleukin-1 and interleukin-6 genes and inhibiting the type I collagen gene. Here we demonstrate that TNF-alpha also stimulates collagenase gene transcription; this stimulation is mediated by an element of the gene that is responsive to the transcription factor AP-1, the major component of which (jun/AP-1) is encoded by the jun gene; and that TNF-alpha stimulates prolonged activation of jun gene expression. This prolonged induction of jun contrasts with its transient activation by the phorbol ester TPA and provides a physiological example of the ability of jun/AP-1 to stimulate its own transcription. This may be a key mechanism for mediating at least some of the biological effects of TNF-alpha.

Mechanisms of differential regulation of interleukin‐6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation

“…As presented here, neither cytokine modulates accumulation of the IL-6 mRNA by interacting with preexisting transcription factors (either repressors or activators) since both TNF alpha and LT require de novo protein synthesis to exert their effects. Induction of transcriptional activators such as AP-1, which has recently been shown to mediate TNF alpha-induced collagenase gene expression in fibroblasts [30] or of Gbinding proteins known to mediate effects of TNF alpha on endothelial cells [31], might also be involved in LT and TNF alpha-modulated IL-6 gene expression. In uninduced as in induced monocytes, IL-6 mRNA is under control of short-lived destabilizers leading to superinduction of IL-6 message as soon as protein synthesis is inhibited.…”

“…In selected experiments cycloheximide (CHX; Sigma, Munich, FRG) (10/~g/ml) was added either 45 min prior to incubation with TNF alpha or LT for 4 h or for a 3-h incubation period that was preceded by 3 h of culture in the presence or absence of TNF alpha or LT. In additional experiments monocytes were exposed to actinomycin D (Sigma, Munich, FRG) (5/~g/ml) for various periods of time (30,60, 90 and 120 min) following a 4-h incubation period with or without TNF alpha or LT. In a third set of experiments, monocytes were incubated with actinornycin D (5/~g/ml) with or without cycloheximide (10 ,ug/ml) for 1 or 3 h, monocytic pathway [20], TNF alpha failed to induce detectable IL-6 mRNA at all concentrations investigated (Fig.…”

Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin

“…Thus, the anticarcinogenic e ect of curcumin may be due to its inhibition of these cellular pathways and suppression of cell growth. Besides cell proliferation, AP-1 and NF-kB are also involved in the cellular reaction to in¯ammatory cytokines such as interleukin-1 and TNF-a (Brenner et al, 1989;Finco and Baldwin, 1995;Muegge et al, 1989), which play important roles in many immune responses. Curcumin's ability to block AP-1 and NF-kB could be a useful tool in controlling in¯ammatory and autoimmune diseases.…”

From receptors to stress-activated MAP kinases

“…Despite the absence of structural similarities between TNF and IL-1b receptors, ligand-induced activation of these receptors leads to overlapping, albeit non-identical, biological functions. One of the important as well as common events triggered by most of these in¯ammatory cytokine receptors is the activation of mitogenactivated protein (MAP) kinases and IkB kinases (IKKs), which ultimately activate various transcription factors such as activator protein 1(AP-1) (Brenner et al, 1989) and nuclear factor-kB (NF-kB) (Rothe et al, 1995a;Baeuerle and Baltimore, 1996;.…”