Skip Navigation

Cardiovascular Research 2006 69(1):7-8; doi:10.1016/j.cardiores.2005.10.009
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Knowlton, A.A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Knowlton, A.A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2005, European Society of Cardiology

NF{kappa}B, heat shock proteins, HSF-1, and inflammation

A.A. Knowlton*

Molecular and Cellular Cardiology, Department of Medicine, University of California, Davis, Davis, CA and Sacramento VA Medical Center, United States

* Molecular and Cellular Cardiology, Genomics and Biomedical Sciences Facility, Rm 6317, University of California, Davis, 451 East Health Sciences Way, Davis, CA 95616, United States. Tel.: +1 530 752 5461; fax: +1 530 754 7167. Email address: aaknowlton{at}ucdavis.edu

Received 26 September 2005; revised 18 October 2005; accepted 25 October 2005

See article by Y. Chen and R.W. Currie [1] (pages 66–75) in this issue.

Investigators are beginning to unravel the intricate relationship between NF{kappa}B, heat shock proteins (HSPs), and heat shock factor (HSF)-1. New information is added to this complex picture with the novel finding that HSF-1 modulates AP-1 activation, adding yet another layer of complexity [1]. HSF-1, a transcription factor for the heat shock proteins, is a key component of the heat shock response. The activation of HSF-1 drives the increase in HSPs in response to injury or stress. NF{kappa}B, a critical regulatory transcription factor, has both pro-inflammatory and anti-apoptotic effects. Activation of the heat shock response yields activation of HSF-1 and increased transcription of the heat shock proteins. The heat shock proteins have an array of protective properties, including refolding denatured proteins, protecting folded proteins and targeting irreversibly denatured proteins for removal. However, it is increasingly evident that there are other mechanisms by which the heat shock response reduces inflammation and injury.

HSF-1 knockout is associated with a chronic increase in tumor necrosis factor (TNF)-{alpha} levels and increased susceptibility to endotoxin [2]. Consistent with this, the promoter for TNF-{alpha} has been found to contain an HSF-1 binding site that represses transcription, and thus loss of this repressor results in sustained expression of TNF-{alpha} [3]. However, there is a reverse action, as well: TNF-{alpha} transiently inhibits activation of HSF-1 via TNF-R1 and activation of phosphatases [4]. Phosphorylation is key to both activation and inhibition of HSF-1, and dephosphorylation, in this case mediated by TNF-{alpha}, can lead to inactivation. In this issue of Cardiovascular Research, Chen and Currie [1] demonstrate that reduction of HSF-1 with iRNA in a vascular smooth muscle cell line amplified the inflammatory response to angiotensin II [1]. Activation of both NF{kappa}B and AP-1 was significantly higher with reduction in HSF-1. HSF-1 has also been reported to block transcription of IL-1β by binding its transcription factor and to block expression of cfos and cfms [5,6,2], which may explain the increased activation of AP-1 with loss of HSF-1. In a mouse model of toxin inhalation, the HSF–/– mice had greater activation of NF{kappa}B, particularly p50, and this was mediated, at least in part, by increased degradation of IKB, suggesting at least one mechanism for increased activity of NF{kappa}B in the absence of HSF-1 [7]. Thus, independent of activation of HSP expression, HSF-1 inhibits transcription of a number of pro-inflammatory genes and modulates the activation of both NF{kappa}B and AP-1. These complex interactions are simplified in the diagram shown in Fig. 1.


Figure 1
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Diagram summarizes key interactions amongst HSF-1, heat shock proteins (HSPs), NF{kappa}B, AP-1 and TNF-{alpha}. HSF-1 inhibits both NF{kappa}B and the expression of TNF-{alpha}. TNF-{alpha} can both activate HSF-1 and inhibit HSF-1. NF{kappa}B can activate HSF-1 and increase expression of HSP72. HSF-1 can inhibit AP-1 activation. Arrow indicates activation. Dashed line stands for a weaker effect. "X" at the end of a line indicates inhibition.

 
HSPs themselves have direct anti-inflammatory and protective effects. Key aspects include protection of protein synthesis, membrane integrity, and mitochondrial function after injury as well as inhibition of apoptosis [8,9]. HSP70 and HSP27 have both been found to decrease NF{kappa}B activation [10]. Knockout of HSF-1 is associated with loss of both basal expression and stress-mediated induction of HSP72 and HSP27 in fibroblasts. In the heart, knockout of HSF-1 has no effect on basal levels of HSP72 and HSP27, but results in loss of the stress-induced increase in these proteins [2].

Paradoxically, in cardiac myocytes, TNF-{alpha} actually induces expression of HSP72 without evidence of injury [11]. TNF-{alpha} may mediate the increase in HSP72 by increasing the binding of HSF-1 [12]. We have found that TNF-{alpha} activates HSF-1 in cardiac myocytes (Chang and Knowlton, unpublished). In both endothelial cells and adult cardiac myocytes, activation of NF{kappa}B was essential for induction of HSP72 expression by estradiol [13,14]. Inhibition of NF{kappa}B activation with DNA binding decoys blocked the protective effects of estradiol treatment. Similarly, NF{kappa}B suppresses TNF-{alpha}-induced apoptosis. Knockout of IKK-β, key for activation of NF{kappa}B, blocked systemic inflammation in a model of intestinal injury, but was associated with severe apoptosis of the mucosa [15]. Thus, TNF-{alpha} and NF{kappa}B exhibit protective, anti-inflammatory, anti-apoptotic properties as well as inflammatory and pro-apoptotic properties.

Clearly, there is a complex interaction among HSF-1, heat shock proteins, NF{kappa}B, and TNF-{alpha}. This interaction may produce fine tuning of the inflammatory response. Much remains to be understood about the interactions among these proteins [2]. The work of Chen and Currie adds new information to our understanding of this interrelationship and shows, for the first time, that AP-1 activation is also modulated by HSF-1 [1].


   References
Top
 References
 

  1. Chen Y., Currie R.W. Small interfering RNA knocks down heat shock factor-1 (HSF-1) and exacerbates pro-inflammatory activation of NF-kappaB and AP-1 in vascular smooth muscle cells. Cardiovasc Res (2006) 69:66–75.[Abstract/Free Full Text]
  2. Xiao X.Z., Zuo X.X., Davis A.A., McMillan D.R., Curry B.B., Richardson J.A., et al. HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice. EMBO J (1999) 18:5943–5952.[CrossRef][ISI][Medline]
  3. Singh I.S., He J.R., Calderwood S., Hasday J.D. A high affinity HSF-1 binding site in the 5'-untranslated region of the murine tumor necrosis factor-alpha gene is a transcriptional repressor. J Biol Chem (2002) 277:4981–4988.[Abstract/Free Full Text]
  4. Schett G., Steiner C.W., Xu Q., Smolen J.S., Steiner G. TNF{alpha} mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response. Cell Death Differ (2003) 10:1126–1136.[CrossRef][ISI][Medline]
  5. Xie Y., Zhong R., Chen C., Calderwood S.K. Heat shock factor 1 contains two functional domains that mediate transcriptional repression of the c-fos and c-fms genes. J Biol Chem (2003) 278:4687–4698.[Abstract/Free Full Text]
  6. Xie Y., Chen C., Stevenson M.A., Auron P.E., Calderwood S.K. Heat shock factor 1 represses transcription of the IL-1beta gene through physical interaction with the nuclear factor of interleukin 6. J Biol Chem (2002) 277:11802–11810.[Abstract/Free Full Text]
  7. Wirth D., Bureau F., Melotte D., Christians E., Gustin P. Evidence for a role of heat shock factor 1 in inhibition of NF-{kappa}B pathway during heat shock response-mediated lung protection. Am J Physiol Lung Cell Mol Physiol (2004) 287:L953–L961.[Abstract/Free Full Text]
  8. Voss M.R., Gupta S., Stice J.P., Baumgarten G., Lu L., Tristan J.M., et al. Effect of mutation of amino acids 246–251 (KRKHKK) in HSP72 on protein synthesis and recovery from hypoxic injury. Am J Physiol Heart Circ Physiol (2005) 289:H2519–H2525.[Abstract/Free Full Text]
  9. Beere H.M., Wolf B.B., Cain K., Kuwana T., Tailor P., Morimoto R.I., et al. Heat shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the apaf-1 apoptosome. Nat Cell Biol (2005) 2:469–475.[CrossRef]
  10. Park K.J., Gaynor R.B., Kwak Y.T. Heat shock protein 27 association with the I{kappa}B kinase complex regulates tumor necrosis factor {alpha}-induced NF-{kappa}B activation. J Biol Chem (2003) 278:35272–35278.[Abstract/Free Full Text]
  11. Nakano M., Knowlton A.A., Yokoyama T., Lesslauer W., Mann D.L. Tumor necrosis factor-{alpha}-induced expression of heat shock protein 72 in adult feline cardiac myocytes. Am J Physiol (1996) 270:H1231–H1239.[Medline]
  12. Watanabe N., Tsuji N., Akiyama S., Sasaki H., Okamoto T., Kobayashi D., et al. Induction of heat shock protein 72 synthesis by endogenous tumor necrosis factor via enhancement of the heat shock element-binding activity of heat shock factor 1. Eur J Immunol (1997) 27:2830–2834.[ISI][Medline]
  13. Hamilton K.S., Gupta S., Knowlton A.A. Estrogen and regulation of heat shock protein expression in female cardiomyocytes: cross-talk with NF{kappa}B signaling. J Mol Cell Cardiol (2004) 36:579–586.[CrossRef]
  14. Hamilton K.L., Mbai F.N., Gupta S., Knowlton A.A. Estrogen, heat shock proteins, and NF{kappa}B in human vascular endothelium. Arterioscler Thromb Vasc Biol (2004) 24:1628–1633.[Abstract/Free Full Text]
  15. Chen L.W., Egan L., Li Z.W., Greten F.R., Kagnoff M.F., K.M. The two faces of IKK and NF-{kappa}B inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia–reperfusion. Nat Med (2003) 9:575–581.[CrossRef][ISI][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Knowlton, A.A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Knowlton, A.A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?