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Institute of Pharmacology, Medical School Hannover, Germany
Correspondence: Dr. Michael Kracht, Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany. E-mail: Kracht.Michael{at}MH-Hannover.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B and JUN-N-terminal protein kinase pathways; and third, stabilization of the mRNA by the p38 mitogen-activated protein kinase pathway. In that way, cells are able to rapidly increase and at the same time, to fine-tune the amount of IL-8 secreted and thereby control the extent of leukocytes attracted to sites of tissue injury.
Key Words: MAPK • NF-B • interleukin-8 • transcription • mRNA stability
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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TRANSCRIPTIONAL REGULATION OF IL-8 |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B element that is required for activation in all cell types studied. NF-B is a dimeric transcription factor composed of a family of five subunits, namely NF-B1 (p50 and its precursor p105), NF-B2 (p52 and its precursor p100), and c-REL, REL A (p65), and REL B [58
]. NF-B is retained in the cytoplasm by its binding to inhibitory (IB) proteins. IB phosphorylation results in ubiquitination and rapid degradation of IBs by the proteasome, allowing NF-B to translocate to the nucleus and bind to DNA. This process is critical for NF-B activation, but enhanced NF-B-induced transcriptional activity might additionally require phosphorylation of the subunits as well as binding of coactivators [58
, 59
]. By using chromatin immunoprecipitation, binding of p65 NF-B to the endogenous IL-8 promoter and subsequent recruitment of RNA polymerase II are found rapidly, within one-half hour of IL-1 stimulation, underscoring the important role of NF-B in IL-8 transcription (Fig. 1
).
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B site, the AP-1 and C/EBP sites are not essential for induction but are required for maximal gene expression [3
4
5
6
7
8
, 10
, 57
, 60
, 65
66
67
].
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B, AP-1 proteins are usually constitutively bound to their cognate DNA element. Transcriptional activity of AP-1 proteins is regulated by their abundance, phosphorylation of transactivation domains, and by their binding to protein kinases [68
, 69
].
It is important to note that in contrast to NF-B, whose p65 subunit binding to the IL-8 promoter has been analyzed at the atomic level [62
], the composition of the endogenous AP-1 dimer as a function of time and stimulus that modulates IL-8 transcription has not been determined.
Little is known about signaling pathways regulating C/EBPs, including the family member C/EBP-ß (also called NF-IL-6), which was found to bind to the IL-8 promoter [60
, 65
66
67
]. Therefore, in this review, we will focus on the role of pathways targeting NF-B and AP-1 in IL-8 gene expression.
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THE ROLE OF PROTEIN KINASE PATHWAYS REGULATING NF-B AND AP-1 IN IL-8 TRANSCRIPTION
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B or AP-1 activity.
The rate-limiting step in NF-B activation—IB proteolysis—is regulated by recently identified IB kinases (IKK
/ß and IKK
/Nemo), which specifically phosphorylate two adjacent serines in IB proteins [70
]. In contrast, the pathway(s) regulating NF-B transactivation, rather than translocation, are less well-defined [59
].
AP-1 is activated by mitogen-activated protein kinases (MAPK). Three MAPK pathways contribute to IL-8 gene expression, the extracellular-regulated protein kinase (ERK), JUN-N-terminal protein kinase (JNK), and p38 MAPK cascades. There are two closely related ERK (1 and 2), three JNK whose differential splicing gives rise to 10 isoforms, and four p38 MAPK isoforms [68 , 69 , 71 , 72 ]. All of them are activated by phosphorylation through dual-specificity MAPK kinases (MKK). ERK are activated by MKK1 or 2, and JNK are activated by MKK7, whereas p38 MAPK are activated by MKK3 and 6. Additionally MKK4 activates JNK and p38 MAPK. MKK require phosphorylation in the conserved kinase domain VIII for activation by upstream kinases (see below).
Several laboratories have used inactive kinase mutants, antisense RNA, or specific inhibitors to block these pathways at various levels in intact human cells to study their contribution to IL-8 gene expression (see Table 1
). No mouse homologue of IL-8 is known today [1
], preventing the analysis of IL-8 expression in mice deficient for any of these signaling molecules. However, information for regulation of IL-6, a cytokine whose expression in many respects is regulated very similar to IL-8 [44
, 59
, 64
], is available from mice deficient in individual components of the pathways activating NF-B and AP-1.
As expected from the essential requirement of the NF-B cis-element for IL-8 transcription, inhibition of NF-B by dominant-negative mutants of IKKß [42
] or IB [40
, 41
] or by antisense to NF-B [37
38
39
] strongly impairs IL-1- and TNF-induced transcriptional expression of IL-8 (see also Table 1
). In line with the importance of NF-B for inflammatory gene expression, inducible IL-6 expression is lost in IKKß- and IKK-deficient mice [73
, 74
].
Compared with NF-B, the role of JNK in IL-8 regulation is less widely explored. However, JNK, like NF-B, are strongly activated under most conditions that induce IL-8. The observation that JNK are in fact essential for IL-8 (and IL-6) expression was made initially in human epithelial cells by blocking JNK activation by stable expression of antisense RNA or by dominant-negative mutants [44
]. The JNK inhibition was specific and did not affect NF-B or p38 MAPK activation [44
]. The absolute requirement of JNK for IL-6 expression was later confirmed in JNK2-/- fibroblasts [73
]. Recently, a reversible ATP-competitive inhibitor, the anthrapyrazolone SP600125, was developed, which preferentially inhibits JNK in vitro (Ki 0.19µM) and at concentrations above 5 µM in vivo. However, at higher concentrations (50 µM), it also inhibited p38 MAPK [75
]. In contrast to the findings above, the inhibitor had no effect on IL-8 expression in lipopolysaccharide (LPS)-stimulated human monocytes [75
]. Therefore, it remains to be seen if it affects IL-8 expression in other systems.
JNK are the only c-JUN kinases identified to date. Therefore, they are generally thought to activate inflammatory genes via c-JUN and the AP-1 cis-element [76 , 77 ]. However, adenoviral expression of a dominant-negative mutant of c-JUN, in which the transactivation domain was deleted, failed to inhibit IL-8 induction in one report [40 ], but this mutant did affect IL-8 expression in another study [46 ]. These findings are consistent with the known variable contribution of the AP-1 site to IL-8 transcription and may point to a less significant role for c-JUN in IL-8 regulation in some conditions [57 ].
Taken together, available data suggest that the NF-B and JNK pathways are indispensable for inducible IL-8 regulation. Blockade of one pathway in the presence of normal activation of the other drastically reduces IL-8 secretion. To further elucidate the individual contribution of NF-B and JNK (and also p38; see below), they were activated in the absence of extracellular stimulation. This was achieved by transient expression of constitutively active protein kinase mutants. Although nonphysiological, this approach allows selective activation of individual pathways alone or in combination. Constitutively active MKK7, a specific activator of the JNK pathway, or NF-B-inducing kinase (NIK), a specific upstream activator of NF-B, induced low IL-8 synthesis and transcription from a minimal IL-8 promotor [13
]. However, MKK7 synergized in both effects with NIK. Activation of the IL-8 promotor by either of the kinases required functional NF-B and AP-1 sites [13
].
What might be the significance of this pathway cooperativity? The cis-elements for NF-B, AP-1, and other transcription factors are located in close proximity within less than 200 base pairs of the IL-8 promoter (refs. [45
, 57
] and Fig. 2
). This suggests the formation of higher-order nucleoprotein complexes. Such a complex, termed transcriptional enhanceosome, has been analyzed in detail for the virus-inducible cytokine interferon (IFN)-ß [78
, 79
]. The purpose of the enhanceosome is to provide a multiprotein surface that makes optimal contact with the proteins of the basal transcriptional machinery and thus facilitates maximal gene transcription [80
]. Contacts between the proteins are enabled or improved by post-translational modifications, chromatin-remodeling via histone acetylation or histone phosphorylation [81
], or large coactivator proteins such as p300/CBP [82
]. The latter provide multidocking platforms and possess intrinsic acetyltransferase activities [83
].
Indeed, recent observations indicate that enhanceosome-like structures modulate IL-8 expression. CBP/p300 potentiates p65-mediated IL-8 transcription in an acetylation-dependent manner [64
], whereas the HDAC-1 negatively affects IL-8 promoter activity [61
]. Using the chromatin immunoprecipitation technique, binding of p65 NF-B and the formation of a TNF-stimulated, preinitiation complex at the IL-8 promoter containing inducibly phosphorylated RNA polymerase II were recently demonstrated [84
].
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THE NUCLEAR PROTEIN NRF IS REQUIRED FOR BASAL AND INDUCIBLE IL-8 TRANSCRIPTION |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B-binding site.
IL-8 expression is low in unstimulated cells. This is partly a result of transcriptional repression of the promoter. By sequence comparison with the IFN-ß promoter, a negative regulatory element (NRE) was found in the IL-8 promoter overlapping partially with the NF-B response element [85
]. NF-B repressing factor (NRF) binds to the IL-8-promoter NF-B-NRE element [45
, 86
]. Reduction of cellular NRF by expressing NRF-antisense RNA results in spontaneous IL-8 gene expression. In contrast, IL-1-induced IL-8 secretion is strongly impaired by expressing NRF-antisense RNA. Mutation of the NRE site results in loss of NRF binding and increased basal IL-8 transcription. Conversely, IL-1-induced IL-8 transcription is decreased by mutating the NRE element. These data provide evidence for a dual role of the NRF in IL-8 transcription. Although in the absence of stimulation, it is involved in transcriptional silencing, in IL-1-induced cells, it is required for full induction of the IL-8 promoter [45
].
The mechanism by which NRF contributes to IL-1-induced IL-8-promoter activation remains elusive. Overexpressed NRF alone did not enhance NF-B-mediated IL-8 transcription. However, when p65 NF-B was expressed together with active nuclear JNK, cotransfected NRF enhanced IL-8 transcription further. These results suggest that NRF is modified itself by a JNK-dependent mechanism or that it is interacting on the IL-8 promoter with kinase-activated transcription factor(s). NRF coactivation required not only an intact NRE site but also binding of NF-B and AP-1 proteins to their cis-elements [45
]. This suggests that the binding of all three transcription factors to their DNA binding sites and their physical interaction is needed for maximal induction of the IL-8 promoter. The NRE overlaps with the NF-B site, and indeed, it was shown previously that NRF is able to interact directly with members of the rel family [86
]. NF-B is modified by protein kinases [87
88
89
], interacts with various proteins that enhance its transcriptional activity [63
, 90
91
92
], and contacts through its C-terminus components of the basal transcriptional machinery [93
]. Thus, it is possible that in IL-1-stimulated cells, NRF enhances NF-B activity in concert with AP-1 by acting on one or more of these mechanisms. The combination of NF-B and NRE sites is conserved in a variety of genes relevant to inflammation [85
, 86
, 94
]. The NRE element does not overlap the NF-B site in all cases. However, it was shown previously that the inhibitory effect of NRE on various NF-B elements is exhibited over distances up to 2.5 kbp [86
]. Thus, it is tempting to speculate that NRF constitutes a major transcription factor, which prevents uncontrolled expression of proinflammatory proteins and contributes to their effective synthesis during disease.
Another mechanism for repression of the IL-8 gene has been described earlier [67
]. In this model, transcription of the IL-8 promoter is induced by replacing the repressor OCT-1 with NF-B and C/EBP as a consequence of IL-1 stimulation [67
]. In contrast to this competitive mechanism, NRF represses the IL-8 promoter, most likely by a noncompetitive mechanism, as it is not replaced by NF-B after stimulation by IL-1 (Fig. 2)
, and as outlined above, it alters its function and is required for maximal promoter activity during stimulation.
As summarized in Figure 2 , these findings are best reconciled with a model, whereby IL-8 transcription is effectively repressed in unstimulated cells by a combination of three mechanisms involving deacetylation of histones [61 , 95 ], OCT-1 binding [67 ], and active repression by NRF [45 ].
Induction of strong IL-8 transcription by the cytokines IL-1 and TNF requires the actively promoted formation of an enhanceosome-like structure at the promoter by at least two signals, one provided by nuclear translocation of NF-B and the other by activation of the JNK pathway. Presumably, through these pathways, the enhanceosome integrates various external signals by a combinatorial usage of a limited set of activators and thereby is able to regulate the magnitude of IL-8 gene transcription (see Fig. 4 ). Further insight into this mechanism requires the identification of all proteins involved, including the target(s) of JNK.
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POST-TRANSCRIPTIONAL REGULATION OF IL-8 BY THE P38 MAPK PATHWAY |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B, is not essential [27
, 29
]. This interpretation is supported by observations made in MKK3- or p38-deficient mice. In these animals, the expression of IL-6 is still inducible by IL-1 or TNF, although to a much lesser extent than in wild-type mice [98
, 99
]. These findings may be explained by the observation that the p38 MAPK pathway regulates a specific, post-transcriptional step in IL-8 gene expression. The very low amount of IL-8 found in unstimulated cells is not only a result of repressed transcription but also the result of a very unstable mRNA. The rapid adenine and uracil degradation of the IL-8 mRNA is mediated by absorbance unit (AU)-rich cis-elements (ARE) contained in its 3' untranslated region. It is interesting that this part of the mRNA is also required for signal-mediated stabilization of the IL-8 transcript. By measuring IL-8 mRNA stability with tetracycline-regulatable reporter gene constructs [13 , 31 , 43 ], it was recently shown that activation of the p38 MAPK pathway stabilizes the IL-8 mRNA. Specifically, these data showed that an active form of MKK6, which selectively activates p38 MAPK, induced marked stabilization of the IL-8 transcript. In addition, an active form of the protein kinase MAPK-activated protein kinase-2 (MK2), a downstream substrate of the MKK6-p38 MAPK pathway, also induced mRNA stabilization, whereas kinase-negative mutants of p38 MAPK or of MK2 interfered with MKK6-induced stabilization. Furthermore, a dominant-negative mutant of p38 MAPK interfered with mitogen-activated ERK kinase kinase 1 (MEKK1) as well as with IL-1-induced stabilization [13 , 31 , 43 ]. NIK and MKK7, which as outlined above, cooperatively induce IL-8 transcription, did not affect degradation of IL-8 mRNA. However, they synergized with MKK6 in induction of IL-8 protein [13 ].
Collectively, these findings indicate that the p38 MAPK pathway contributes to cytokine/stress-induced IL-8 gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism (Figs. 3 and 4 ).
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REGULATION OF IL-8 EXPRESSION BY THE ERK PATHWAY |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B, JNK, and p38 pathways in IL-8 gene regulation has been analyzed in detail, information about the role of other signaling molecules (MKK1) is very limited (see Table 1
). Based on use of the MEK1 inhibitors PD9805 and U0126, there is some evidence that the ERK pathway contributes to IL-8 expression (Table 1)
. We found that EGF, a physiological activator of ERK, weakly induces IL-8 in a JNK- and NF-B-independent manner [13
]. Furthermore, expression of a constitutively active mutant of MEK1 causes some IL-8 transcription but fails to induce significant IL-8 protein (M. Kracht and E. Hoffmann, unpublished observations). These data suggest that the ERK pathway on its own is not a very potent inducer of IL-8 but has the potential to contribute to IL-8 induction stimulated by NF-B and other pathways. |
COORDINATED ACTIVATION OF THE NF-B, JNK, AND P38 MAPK PATHWAYS BY MAPKK KINASES (MAPKKK) STRONGLY INDUCES IL-8
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B and at least one or two MAPK pathways. This raises the question of how cytokine receptors coordinate this activation. MAPKKK comprise a remarkably large group of distinct enzymes, namely Raf-1, A-Raf, B-Raf, Mos, NIK, MEKK1–4, MLK2, MLK3, DLK/MUK, ASK1, Tpl-2/Cot, and transforming growth factor-ß-activated protein kinase 1 (TAK1). Although structurally quite different, MAPKKK phosphorylate and activate MAPKK and thereby activate MAPK. The JNK and p38 MAPK signaling pathways can be activated by ectopically expressed MEKK1–4, MLK2, MLK3, DLK/MUK, ASK1, Tpl-2/Cot, and TAK1, albeit to varying degrees [102 ].
IKK are activated by phosphorylation of serine 176 and 180 in the T-loop of the kinase domain [103
]. This motif resembles the regulatory sequence in MAPKK, which is phosphorylated by MAPKKK. In agreement with that observation, an increasing number of MAPKKK have been shown recently to phosphorylate IKK and activate NF-B. Of those, MEKK1, 2, and 3, Tpl-2/Cot, and TAK1 also activate JNK and p38 MAPK, and NIK is the only NF-B-specific MAPKKK [13
, 31
, 43
, 45
, 100
101
102
, 104
]. Thus, apparently some MAPKKK, like cellular stress or the proinflammatory cytokines IL-1 or TNF, can trigger two or three stress-kinase pathways simultaneously. However, knowledge is still limited as to which of the many MAPKKK link these pathways to the receptors for physiological inducers of IL-8, such as IL-1 or TNF [104
].
It is interesting that the MAPKKK, MEKK1, and TAK1, which can activate NF-B, JNK, and p38 MAPK, very potently induce IL-8 formation [13
, 43
, 45
]. Furthermore, both kinases are activated by oligomerized adaptor proteins, TNF-receptor-associated factors (TRAF)-2 or -6, respectively. TRAFs link the IL-1 or TNF receptors to cytosolic signaling pathways by, so far, poorly characterized mechanisms [32
, 100
].
Evidence for a central role of the TAK1 protein kinase in IL-8 expression was found recently. Expression of a kinase-inactive mutant of TAK1 largely blocked IL-1- or TNF-induced transcription and mRNA stabilization (ref. [43 ], and M. Kracht and J. Enninga, unpublished observations).
Activation of TAK1 is crucially dependent on interaction with the adaptor protein TAB1 [100
]. A truncated version of TAB1, lacking the TAK1-binding domain, or a TAK1-derived peptide containing a TAK1-autoinhibitory domain was also efficient in inhibition. TAB1-activated TAK1 induced IL-8 transcription, mRNA stabilization, and protein formation [43
]. These data establish the TAK1-TAB1 complex as an intracellular effector that controls the main steps of IL-8 gene expression. Additional experiments showed that downstream of TAK1, signaling diverges to regulate distinct steps in IL-8 expression. TAB1-TAK1-induced transcription was blocked by a kinase-inactive mutant of JNK2, whereas a kinase-inactive mutant of p38 MAPK had no effect. Conversely, TAB1-TAK1-induced mRNA stabilization was blocked by a kinase-inactive mutant of p38 MAPK but not by a kinase-inactive mutant of JNK2. Thus, downstream of active TAK1, NF-B and JNK2 as well as p38 MAPK are targeted to distinct gene-regulatory functions by, so far, unknown mechanisms [43
].
These results provide evidence that maximal IL-8 gene expression requires the coordinate action of at least three different signal transduction pathways that cooperate to induce mRNA synthesis and suppress mRNA degradation. Importantly, this three-pathway model of IL-8 induction is operative in response to a physiological stimulus IL-1, and the MAPKKK TAK1 plays a central and nonredundant role in coupling the IL-1 receptor to transcriptional and RNA-targeted mechanisms mediated by the three pathways [13 , 31 , 43 , 45 ].
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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B and JNK pathways are activated to induce transcription, and the resulting mRNA is rapidly stabilized by the p38 MAPK pathway (Figs. 3
and 4)
. In that way, cells are able to rapidly increase and at the same time, to fine-tune the amount of IL-8 secreted and thereby control the extent of leukocytes attracted to sites of tissue injury. The components of the involved pathways are not only ubiquitously expressed but are also activated by numerous stimuli, a fact that explains why so many cells are capable to react with a uniform, biological response, i.e., IL-8 secretion to external challenge. It is also important to note that the type of signal-dependent gene expression described here is not restricted to IL-8 but may also be relevant for many other proteins, e.g., IL-6 expressed during an inflammatory response. Therefore, therapeutic targeting of the production of IL-8 (and of other inflammatory proteins) may most effectively be achieved by inhibiting key intracellular signaling molecules.
Received March 25, 2002; accepted April 23, 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONTRANSCRIPTIONAL REGULATION OF IL...THE ROLE OF PROTEIN...THE NUCLEAR PROTEIN NRF...POST-TRANSCRIPTIONAL REGULATION...REGULATION OF IL-8 EXPRESSION...COORDINATED ACTIVATION OF THE...CONCLUSIONSREFERENCES |
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