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Microbes & Immunity RANTES/CCL5 and ezrin peptide RepG3 for long COVID

factors are required for its full activation. The promoter of the lung, IRFs act synergistically with NF-κB to induce
region extends back from the transcription start-codon RANTES/CCL5 mRNA expression, protein translation,
and contains seven distinct transcription factor binding and secretion. In fibroblasts, epithelial cells, and endothelial
sites (“C”-“D”-“E”- “CAAT”-“A”-“B”-“TATA”-“Start”), also cells, interferon-gamma (INF-γ) regulates RANTES/CCL5
known as cis-regulatory elements. mRNA stabilization but does not trigger RANTES/CCL5

Transcription factor CREB is important for RANTES/ mRNA expression.
CCL5 transcription and binds to the “E”-site of the 5.3. Induction of RANTES/CCL5 expression by IL-1 β
RANTES/CCL5 promoter between −220bp and −190bp,
the location of an important “cyclic AMP-responsive In epithelial cells of the mucosa, endothelial airway
element” (CRE). CREB is responsible for most of the basal cells, fibroblasts, monocytes, and macrophages,
transcriptional activity and half of the RANTES/CCL5 proinflammatory IL-1β enhances RANTES/CCL5 mRNA
mRNA expression in response to viral infection. 73 expression, protein translation, and secretion within a few
hours. The binding of transcription factors to different
In infection by RSV, full transcriptional activation of the combinations of cis-regulatory DNA-elements of the
RANTES/CCL5 gene in alveolar epithelial cells requires gene promoter of CCL5 is required for optimal levels of
multiple transcription factors binding to the DNA of its RANTES transcription in different cell types. For example,
cis-regulatory elements. RSV induction of RANTES/CCL5 in the proinflammatory activation of T lymphocytes by
gene transcription requires CREB-binding CRE as part of IL-1β, the binding of transcription factors NF-κB, NF-IL-
the multi-protein transcription complexes with c-Jun and 6, and NF-AT to cis-regulatory elements in the promoter
the coactivators CBP and p300. In addition, interferon of the RANTES/CCL5 gene is necessary. In NIH3T
regulatory factors (IRF-1, IRF-3, or IRF-7) bind to the fibroblasts, the binding of transcription factor NF-κB to
interferon-stimulated responsive element (ISRE), located at the NF-κB-response-element 30 bp upstream of the CCL5
–138bp to –117bp in the promoter region of the RANTES/ gene plays a dominant role in mRNA transcription and
CCL5 gene. In contrast, in Sendai virus induction of increases RANTES/CCL5 gene transcription into mRNA
RANTES/CCL5 gene transcription, significant activation by 40 times. 77
requires the combined action of NF-kB (p65/p50) and IRF-
3. Additional stimulation is also provided by transcription 5.4. Delayed induction of RANTES/CCL5 expression
factors NF-IL6 and C/EBP binding to the promoter region in T-cells
between −100 bp and −39 bp of the RANTES/CCL5 gene. 74
T-cells respond to antigen-MHC or mitogen triggering
5.2. Induction of RANTES/CCL5 expression by TNF-α by producing RANTES/CCL5 protein after a 3-day
delay. This delayed expression is controlled by a
The pattern of transcription factors involved in specific transcription factor called “RANTES Factor
proinflammatory cytokine induction of RANTES/CCL5 of Late Activated T Lymphocytes-1” (RFLAT-1), a
gene expression differs from the pattern of transcription 31-kD phosphorylated zinc-finger transcription factor.
factors triggered by viral infection. In fibroblasts, epithelial However, this transcription factor resembles a Krüppel-
cells, monocytes, macrophages, and human pulmonary like transcription factor, so RFLAT-1 has been recently
vascular endothelial cells of the lung, 1 – 100 ng/mL renamed KLF13. To avoid confusion in this review, the
proinflammatory cytokine TNF-α induces dose-dependent transcription factor responsible for delayed RANTES/
RANTES/CCL5 expression and secretion, which peaks CCL5 expression in activated T-cells is hereinafter
48 h after treatment. 75 referred to as RFALT-1/KLF13. The transcription factor
TNF-α stimulation triggers RANTES/CCL5 mRNA RFALT-1/KLF13 specifically binds to the −71 bp to
expression through phosphorylation and activation of −53 bp “A” site of the RANTES/CCL5 gene promoter as
p38 mitogen-activated protein kinase (p38 MAPK), which a component of a multi-protein transcription complex.
activates IKK, which knocks-out inhibitor IκB, allowing In contrast, the transcription factor CREB binds to
transcription factor NF-κB subunits p65 and p50 to –115bp to –91bp of the “E” site, and NF-κB mainly binds
migrate to the nucleus and transcribe the RANTES/CCL5 to the −53 bp to −43 bp “B” site of the RANTES gene
gene into mRNA. The p38 MAPK inhibitor SB-203580 promoter. 78
inhibits TNF-α-induced p38 MAPK activity and prevents In both resting and activated T lymphocytes, the levels of
NF-κB-mediated mRNA transcription of the RANTES/ gene expression of RFLAT-1/KLF13 into mRNA remained
CCL5 gene. 76 constant. However, for 3 days after activation by antigen-MHC
IRF-1 and IRF-3 are major components of the TNF-α- triggering, a specific protein-translation control mechanism
induced transcription complex. In alveolar epithelial cells imposes temporal regulation by inhibiting RFLAT-1/KLF13

Volume 1 Issue 1 (2024) 13 doi: 10.36922/mi.2474