Ocular Immunology and Inflammation

ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20

Roles of IL-6 in Ocular Inflammation: A Review

Hassan Ghasemi

To cite this article: Hassan Ghasemi (2017): Roles of IL-6 in Ocular Inflammation: A Review,
Ocular Immunology and Inflammation, DOI: 10.1080/09273948.2016.1277247

To link to this article: http://dx.doi.org/10.1080/09273948.2016.1277247

Published online: 01 Feb 2017.

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Ocular Immunology & Inflammation, 2017; 00(00): 1–14
© Taylor & Francis Group, LLC
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.1080/09273948.2016.1277247

REVIEW ARTICLE

Roles of IL-6 in Ocular Inflammation: A Review

Hassan Ghasemi, MD

Department of Ophthalmology, Shahed University, Tehran, Iran

ABSTRACT
Purpose: This review represents the current in vitro, in vivo animal and human researches on the roles of IL-6 in
inflammatory ocular disorders. Data sources were literature reviewed using PubMed, Medline, and ISI Databases
(since 1981 to late 2016). Search items included interleukine-6 (IL-6); chemokine; cytokine, alone or in combina-
tion with serum, aqueous, vitreous, eye, ocular, ophthalmic, and review.
Results: IL-6 is found to be involved in ocular inflammation. Ocular effects of IL-6 differ based on the source of
the secretion and site of the action. The most important effects of IL-6 in the eyes are angiogenic activities and
induction of ocular inflammation.
Conclusion: IL-6 plays an important role in ocular inflammation and angiogenesis in conjunctiva, cornea, iris,
retina, and orbit. Anti-IL-6 targeted immunotherapy has recently been employed as an important treatment
modality in IL-6-related ocular disorders, provided that IL-6 signal blocking takes place in preferred and favorite
targets.
Keywords: Chemokine, cytokine, interleukine-6, ocular inflammation, review

Interleukin (IL)-6 was successfully cloned first in 1986
as B-cell stimulatory factor-2 (BSF-2), that stimulates B
cells to produce immunoglobulin. At the same time,
structurally identical molecules to IL-6, interferon
(IFN)-beta 2 and a 26 kDa protein were found in
fibroblasts. Later, two other molecules similar to IL-6
known as a hybridoma/plasmacytoma growth factor
and a hepatocyte-stimulating factor were discovered.
Thereafter, the role of the IL-6 receptor (IL-6R) system
and the IL-6 signal transduction mechanism were clar-
ified in immune regulation, hematopoiesis, inflamma-
tion, and oncogenesis.1 Cytokines normally function as
autocrine and paracrine regulatory hormones for cell
growth, differentiation, function, inhibition, and apop-
tosis. Type I cytokines include immunoregulatory
cytokines (IL-2, -4, -7, -9, and -15); hemopoietic cyto-
kines (IL-3, -5, and granulocyte-macrophage colony
stimulating factor (GM-CSF)); cytokines related to
cytokinesis of hematopoietic system, immune systems,
cardiovascular, and central nervous systems (IL-6, IL-
11, oncostatin M or OSM); leukemia inhibitory factor
(LIF), ciliary neurotrophic factor (CNTF); and cardio-
trophin-1 involving a common glycoprotein (gp) 130
receptor in various inflammatory or tumoral diseases
through tyrosine kinases activation and finally cellular
immunity and hemopoiesis cytokines (IL-12, -21, and
-23). Type II cytokines (type I IFN-α, β, and ω, type II
IFN-γ and IL-10) suppress the inflammation.2 IL-6 in
accordance with proinflammatory cytokines, tumor
necrosis factor (TNF) and IL-1 family, mediates acute
inflammation and multifold activation of natural
immune mechanisms and major metabolic alterations
within 24–48 h, the condition that is called immuno-
conversion with growth hormone, prolactin suppres-
sion, glucocorticoids, and catecholamine elevation.3 In
the acute-phase of inflammation, IL-6-type cytokines
including IL-6, IL-11, LIF, as well as OSM, CNTF,
cardiotrophin-1, and cardiotrophin-like cytokine med-
iators (all as a family of mediators) are involved and
share the same gp130 signal transducer chain. Any
abnormalities in IL-6-type cytokine signaling may
induce several disorders and various types of cancer4
(Figure 1). Macrophages are able to synthesize many
cytokines including IL-1, IL-1 receptor antagonist (IL-
1ra), IL-6, IL-8, IL-12, TNF-α, IFN-α, IFN-γ, monocyte
chemoattractant protein (MCP-1), MCP-3, macrophage

Received 7 October 2016; revised 22 December 2016; accepted 23 December 2016; published online 1 February 2017
Correspondence: Hassan Ghasemi, MD, Department of Ophthalmology, Medical School, Shahed University, P.O. Box 14155-7435, Tehran, Iran.
E-mail: ghasemi518@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ioii.

1
2 H. Ghasemi

FIGURE 1. Schematic structure and roles of IL-6 in health and disease.

FIGURE 2. Biologic roles of IL-6 in animals and humans. APP, amyloid precursor protein; PC12, cell line–derived from a pheochro-
mocytoma of the rat adrenal medulla.

migration inhibitory factor (MIF), macrophage colony
stimulating factor (M-CSF), granulocyte colony stimu-
lating factor (G-CSF), GM-CSF, macrophage inflamma-
tory protein (MIP)-1 and 2, and transforming growth
factor (TGF)-β.5
Detailed reviews on IL-8 and IL-10 effects in ocular
inflammation have previously been published,6, 7 but
there were not any detailed ocular-related IL-6 review
in the medical literature. The purpose of this review
was to elucidate the complexity and the functional
diversity of IL-6 in ocular inflammatory disorders.
MATERIALS AND METHODS
PubMed, Medline, and ISI databases (since 1981 to late
2016) were searched for articles published during
1981–late 2016. The keywords searched included IL-6,

Ocular Immunology & Inflammation


cytokine, chemokine, alone or in combination with the
in vitro, in vivo, serum, aqueous, vitreous, eye, ocular,
ocular tissues, ophthalmic, and review. More than 100
000 items related to IL-6 were found in different data-
bases. Of them, more than 1500 articles in relation to
the eye, ocular, and ophthalmic items were considered
as the general basic data framework. About 550 papers
were more relevant to the eyes that were considered as
IL-6 databank and finally of those, 175 full-text articles
were selected for this review. The selected language
was in English. In vitro and in vivo ocular studies on
animals and humans were included to review the
mechanisms of action and clinical effects of IL-6.
3IL-6 BIOLOGY
IL-6 plays an active role in growth and differentiation
activities on B cells, myeloma plasmacytomas, T cells,
hepatocytes, and hematopoietic stem cells with dual
binding affinities to high-affinity receptors and low-
affinity receptors. Structural elements of the 80 kDa
receptor protein showed similarity to both the hema-
topoietic growth factor receptor (HGFR) family and
the Ig supergene family.8 Chemokine receptors as the
essential co-stimulatory molecules are associated with
different disorders and found on many blood cells
including mast cells. Co-stimulation of murine bone
marrow-derived mast cells significantly increased
mast cell secretion of growth factors, cytokines and
chemokine including TGF-β1, TNF-α, and IL-6.9
Shortly after TNF-α, IL-1, IL-6, and IL-8 secretion, IL-
10 appears in monocytes and suppresses the produc-
tion of these proinflammatory cytokines.10 Lack of IL-4
in IL-4_/_ mice leads to decreased IL-6 and IL-10 and
increased IFN-γ secretions.11 IL-6 stimulates the pro-
duction of IL-4 and then helper T subset (Th)-2 cyto-
kines, such as IL-10 during Th2 differentiation.12 Th17
cells require IL-6 and TGF-β for lineage commitment
and IL-23 for maintenance.13 B-cell response into anti-
body-producing cells needs three distinctive regula-
tory factors: (1) a resting B cells activating factor
(BSF1/IL-4), (2) an activating B cells growth factor
(BCGFII/IL-5), and (3) B cells maturation into anti-
body-producing cells factor (BSF2/IL-6). BSF2/IL-6 is
also a potent growth factor for myeloma cells and a
hepatocyte-stimulating factor for generation of acute-
phase proteins and multi-colony stimulating factors to
activate hematopoietic stem cells. BSF2/IL-6 plays
essential roles in host defense mechanisms against
inflammation, infections, and injuries (Figure 2).14
IL-6 SUPER FAMILY
The IL-6 cytokine families contain a helical structure
and their receptors are related to the type 1 cytokine
receptor family that induces growth or differentiation
© 2017 Taylor & Francis Group, LLC
IL-6 and Ocular Inflammation 3
through gp130 subunit. IL-6 belongs to a family of
cytokine including interleukin-11, LIF, OSM, cardiotro-
phin-1, and ciliary neurotrophic factor. IL-6 as a multi-
functional cytokine plays immune and hematopoietic
activities in acute phase of host defense. Selective
antagonists of IL-6 may induce therapeutic effects.15
IL-6, TGF-β, IL-23p19, IL-23p40, CD4, CD8, major his-
tocompatibility complex I (MHC I), MHC II, IL-17, IL-
17F, interleukin 17 receptor A (IL-17RA), retinoic acid-
related orphan receptor gammat (RORgammat), and
chemokine receptor 6 (CCR6) belonged to the group of
Th17-associated molecules.16
IL-6 SOURCES AND INTERACTIONS
Many inflammatory cytokines including IL-6 are pro-
duced and released by a variety of cell types, espe-
cially macrophages and monocytes,17 vascular smooth
muscle cells,18 and osteoblasts,19 but only few of them
including macrophages, neutrophils, some types of
T-cells and hepatocytes express IL-6R on their cell
surfaces and therefore respond to IL-6 alone. In con-
trast, gp130 is universally expressed in all tissues and
cells.20 The Gpl30 protein molecule belongs to the
hepatocyte growth factor (HGF) receptor family.21
STAT proteins transcriptional regulation is controlled
via C-terminal domains, both through tyrosine and
serine phosphorylation site. Protein kinase C delta
(PKC delta) phosphorylates and interacts with STAT3
in an IL-6-dependent manner. The initial step for
STAT3 activation by IL-6 begins with interaction of
catalytic domain of PKC delta with Src homology 2
domains and partly with adjacent C-terminal transac-
tivation domain of STAT3 and enhances with the inter-
action of STAT3 and the IL-6 receptor subunit
glycoprotein (gp) 130.22 Three topologically different
receptor binding sites have been recognized for IL-6:
site 1 has been specified for binding to IL-6Rα chain,
and sites 2 and 3 have developed for interaction with
two subunits of the gp130 signaling chain (Figure 3).23
IL-6 STRUCTURE, RECEPTORS, AND
SIGNALING
IL-6 structure contains 185 amino acid polypeptides.24
IL-6 is a glycosylated protein of 21–28 kDa with a four
long alpha helix bundles (A, B, C, D) with an up–up–
down–down topologic arrangement and contains
three receptor-binding sites including site 1 for connec-
tion with IL-6R, site 2 located between domain (D) 2
and 3 for interaction with gp130, and site 3 for con-
nection with domain 1 or Ig-like domain of gp130. The
C-terminal residues of helix D and the C-terminal of
AB-loop formed site 1. Residues located in the middle
of helices A and C formed site 2, and residues located
at the N-terminal part of the AB-loop (site 3a) and the
4 H. Ghasemi
FIGURE 3. Structure of the complete ectodomain receptor signaling complex of IL-6 with IL-6Rα, and gp130, derived from electron
microscopy and crystallography data included domain sites (D): 1, 2, and 3.
C-terminal residues of the D helix (site 3b) formed site
3 for connection with two gp130 molecules.20 Any
mutations especially in three important sites of IL-6,
especially the beta-site, can separate receptor binding
from signal transduction and interaction with gp130.25
Two molecules of each components (dimerization), of
IL-6 and its receptor (R), form a hexameric complex
that increased affinity for the IL-6R but decreased
ability to couple with gp130 and may be an efficient
IL-6 antagonist.26
With a soluble component (s) and its receptor (R)
and gp130, IL-6 forms the low-affinity complex (IL-6.
sIL-6R) or alpha-subunit and the high-affinity complex
(IL-6.sIL-6R.sgp-130) or beta-subunit that forms the
monomeric type of IL-6.27 Activation of cells that
only express gp130 on their surface (such as hepato-
cytes, neutrophils, monocytes/macrophages, and cer-
tain other leukocyte populations) via the IL-6/sIL-6R
complex is called trans-signaling, whereas activation
of cells via the membrane-bound non-signaling α-
receptor IL-6R (mbIL-6R) in complex with IL-6 is
called classic-signaling.28,29 An auxiliary signaling
molecule in IL-6–gpl30 complex structure (IL-6Rβ
chain) converts the low-affinity to high-affinity
binding.21,30 The most specific step in the IL-6 signal-
ing pathway is interaction between IL-6 and IL-6R that
consists of two parts of hydrophobic core and hydro-
philic residues.31 The receptor complexes needed for
IL-6 activity include gp130, IL-6, LIF, and OSM.
Meanwhile, a monoclonal antibody (mAb) to the Ig-
like module forms part of gp130 that can neutralize the
bioactivity of IL-6, but not of LIF or OSM.32 The acute
phase response includes a local phase and a systemic
phase that by itself consists of an acute plasma pro-
teins phase concentration. Subsequently, the signal
transducers and activators of transcription (STATs) 1
alpha and STAT3 interact with JAK kinases and
gp130.33 In human body, all cells express gp130 but
not all of them express the human IL-6 receptor (hIL-
6R). Human IL-6 could not stimulate cells without hIL-
6R. However, a natural soluble human IL-6 receptor
(shIL-6R) binds to hIL-6 (hIL-6/shIL-6R) and stimu-
lates cells without hIL-6R (trans-signaling process)
and increase the inflammation and cancer rate.34
Since sIL-6R could also be induced naturally, cells
only expressing the gpl30 but lacking IL-6R may
respond to sIL-6R/IL-6 complexes and gpl30 could
even act as a secondary protein for the OSM and LIF
receptors.35,36
ROLE OF IL-6 AND IL-6R IN OCULAR
ANGIOGENESIS
Along with the other angiogenic factors including
IL-8, vascular endothelial growth factor (VEGF),
angiogenin, MCP-1, and TGF-β1, IL-6 has clinically
important angiogenic activities.37 There are some
clinical instances for this capability.
Proinflammatory cytokines such as IL-6 and TNF-α
provoke angiogenesis and lymphangiogenesis
through increased expression of VEGF and matrix
metalloproteinases (MMP)-9 in herpetic stromal
keratitis (HSK).38 Serum and vitreous amyloid A
that can regulate angiogenesis and IL-6 as proin-
flammatory factors may be involved in retinal
angiogenesis and progression of proliferative dia-
betic retinopathy (PDR).39 Regardless of diabetic
retinopathy (DR), IL-6 and VEGF play important
roles in retinal angiogenesis in Eales’ disease.40
Ocular Immunology & Inflammation

NORMAL HUMAN TEAR IL-6 VALUES
Multiplex bead-based assays technique showed that 25
cytokines/chemokines are detectable in the tear of
normal subjects. The tear levels of IL-6 were between
100 and 400 pg/ml.41 Sharma reported that the mini-
mal detectable value of IL-6 was 5.81 pg/ml.42
OCULAR EFFECTS OF IL-6 IN HUMAN
Ocular Surface and Corneal Effects
In patients with dry eye disease, tear cytokines of IL-2,
IL-4, IL-5, IL-6, IL-10, IFN-γ, TNF-α, IL-1β, and 1 che-
mokine IL-8 levels significantly overproduced in par-
allel with the severity of the disease,43 but only sIL-6R,
sIL-6Rsgp130, in conjunction with IL-1β are the poten-
tial indicators for dry eye disease.44 Also in Sjogren
disease, tear IL-1Ra, IL-6, IL-8, and MMP-9 are signifi-
cantly overexpressed.45 In dysfunctional tear syn-
drome (DTS), irritation symptoms had a significant
correlation only with IL-6 tear concentration.46 Tear
film IL-6 levels were negatively correlated with
Schirmer test and tear lysozyme levels, but were posi-
tively correlated with conjunctival staining.47 Tear
fluid levels of IL-6 and IFN-γ significantly increased
in patients with ocular graft-versus-host disease
(GVHD).48 The levels of IFN-γ correlates with
Schirmer score and tear break up time, and IL-6 level
correlates with dry eye, tear production, corneal stain-
ing, and ocular surface disease index (OSDI) score.49 In
DTS, besides MMP-9 that is a useful tear biomarker for
diagnosis, classification, and monitoring of patients,
conjunctival epithelia levels of IL-1β, IL-6, TNF-α, and
TGF-β1 mRNA transcripts are significantly higher than
the normal subjects.50 In recurrent corneal erosion, IL6
gene-174C allele has been introduced as a genetic
marker for corneal erosion risk in hereditary stromal
corneal dystrophies.51 In early progressive stages of
Pseudomonas aeruginosa keratitis, only Toll-like recep-
tors (TLR)-9 and nuclear factor kappa light-chain
enhancer of activated B cells (NF-κB) inhibitor alpha
were elevated. But later, TLR-2, -4, -5, -9, IL-6, IL-8,
and myeloperoxidase activity increased to control the
progression of infection.52
More intensive inflammatory response encountered
in photorefractive keratectomy (PRK) than laser-
assisted in situ keratomileusis (LASIK) was identified
with increased tear concentrations of TNF-α, IL-1β, IL-
6, and IL-8.53 Tear levels of IL-6, IL1b, and IFN-γ are
elevated in patients with keratoconus (KCN).54 Tear
proteolytic activity and overexpression of several
MMPs and cytokines including IL-6 increased in
patients with KCN but tear IL-6 is the only cytokine
that was significantly increased in patients with KCN
compared with the collagen cross-linked patients.55
© 2017 Taylor & Francis Group, LLC
IL-6 and Ocular Inflammation 5
Meanwhile, in patients with KCN tear fluids levels of
IL-6 and IL-17 increased, indicating degenerative
processes.56 IL-6 plays an important role in ocular sur-
face immune defense and decreases the severity and
susceptibility of contact lens–related keratitis.57
Tear IL-6 and IL-8 levels increased in parallel with
the severity and stages of the diseases in patients with
conjunctivochalasis.58 In atopic keratoconjunctivitis
(AKC), conjunctival irritations induced by airborne
allergens leads to significant increase in tear IFN-γ
and IL-6 levels.59 IL-6 and IL-15 of conjunctival
mucosa are risk factors for chronic scarring trachoma
with increased levels for concurrent chlamydia tracho-
matis infections.60 IL-8, and to some extent, IL-6, and
VEGF are expressed by pterygium epithelium that is
enhanced by UV exposure.61 Conjunctiva of patients
with ocular cicatricial pemphigoid (OCP) showed stro-
mal overexpression of IL-6 compared with normal
conjunctiva.62 Conjunctival epithelial IL-6, IL-8, and
IL-10 expression is significantly increased in patients
with glaucoma.63 In patients with primary open angle
glaucoma (POAG), serum levels of IL-4 and IL-6 were
higher than the controls.64 Iris from patients with neo-
vascular glaucoma (NVG) showed higher IL-6 levels
than POAG.65 In early pseudoexfoliation (PEX) syn-
drome, IL-6 and IL-8 mRNA expression significantly
increased in ciliary process and iris. Ciliary processes
are the most potential source for aqueous IL-6 and IL-8
(about 100 times higher than that of all other normal
ocular tissues).66
Uveal Effects
Immune-mediated uveitis, with or without a systemic
disease, is responsible for 10% of all blindness in
patients under the age of 65 years. Proinflammatory
cytokines including IL-6 play pivotal roles in many
types of uveitis.67 Indeed, the so-called anterior cham-
ber-associated immune deviation (ACAID) loop that
consists of spleen, an intact sympathetic nervous sys-
tem and aqueous humor TGF-β, could be antagonized
by IL-6 anti-TGF-β activity.68 For the first time Murray
et al.69 showed that in some types of uveitis, such as
Fuchs heterochromic iridocyclitis and toxoplasma
uveitis, aqueous humor levels of IL-6 significantly
increased independently from serum IL-6 alteration.
Later, Malecaze et al.70 showed that the aqueous IL-6
plays a significant role in cataract surgery–induced
uveitis by the same mechanism. Aqueous humor-acti-
vated T lymphocytes are increased in Vogt–Koyanagi–
Harada (VKH) disease and sarcoidosis, which in turn
increased aqueous levels of IL-6 and exacerbates the
inflammation independently from serum T
lymphocytes.71,72 Nevertheless, serum levels of IL-8
and IL-6 are significantly increased in patients with
active uveitis but decreased during remission. IL-8
6 H. Ghasemi
levels were higher in patients with anterior and acute
uveitis, while IL-6 is higher in chronic uveitis.73 In
patients with rejected penetrating keratoplasty (PK),
significant increase in tear IL-6/IL-10 and IL-8/IL-10
ratios are important indicators for corneal endothelial
rejection during follow-up.74 Aqueous IL-1β, IL-6, and
prostaglandin (PG) E2 significantly increased after
femtosecond laser-assisted cataract surgery that may
be the cause of intraoperative miosis during the
surgery.75
Aqueous humor (AqH) levels of IL-6, IL-8, and
MCP-1 in patients with cataract and open-angle glau-
coma increased simultaneously.76 In glaucomatous
patients, higher pre-operative aqueous humor TNF-α
and IL-6 levels are associated with worsening in out-
come of glaucoma surgery.77 Aqueous humor levels of
IL-6, IL-8, and IL-1β are significantly increased in eyes
with uveal melanoma and after brachytherapy and
adjunctive transpupillary thermal therapy (TTT).78 In
patients with major branch retinal vein occlusion
(BRVO) and to some extent in macular BRVO, aqueous
IL-6, IL-8, VEGF, platelet-derived growth factors
(PDGF)-AA, and MCP-1 levels are significantly ele-
vated. Frequent intravitreal injections of bevacizumab
improved macular edema by decreased production of
these cytokines.79 IFN-γ, IL-6, and MIP-1β are the com-
mon markers in AqH in patients with ocular toxoplas-
mosis and viral uveitis.80 Significant elevation of a
variety of angiogenic, inflammatory, and chemotactic
cytokines in aqueous and vitreous of eyes with uveal
melanoma support the relationship between inflam-
mation and tumors formation. IL-6, IL-8, MCP-1, and
VEGF are correlated with tumor dimensions.81 In
uveal melanoma, vitreous IL-6 and IFN-γ-inducible
protein 10 (IP-10) levels increase with regulatory
T-cell infiltration and only IL-6 is positively correlated
with macrophage infiltration.82 In intermediate uveitis
(IU), especially with cystoid macular edema (CME)
and active disease, IL-6 and IL-8 are significantly
increased.83 In Behcet’s disease, retinal S antigen and
interphotoreceptor retinoid binding protein (IRBP)
play important roles in the development of uveitis
through stimulation of IL-6, IL-17, and IFN-γ
production.84 In patients with uveitis, AqH concentra-
tion of soluble gp130, a natural antagonist of IL-6
trans-signaling, is increased significantly with disease
severity and partially inhibits the process of IL-6 trans-
signaling during inflammation.85
Vitreous and Retinal Effects
An inflammatory-immune process is involved in the
pathogenesis of PDR.86 In DR, AqH levels of IL-6 and
VEGF significantly increased and may be useful indi-
cators for early detection and prognosis of DR.87
Increased retinal veins caliber are associated with
higher serum C-reactive protein (CRP), IL-6, and
amyloid A levels.88 In PDR with fibrovascular mem-
branes, serum and vitreous levels of amyloid A sig-
nificantly correlate with IL-6 levels.39
In eyes with DR, aqueous levels of IL-6 are posi-
tively correlated with total macular volume and cen-
tral subfoveal macular thickness.89 Aqueous and
vitreous levels of IL-6, IL-8, VEGF, and MCP-1 were
increased in all patients with central retinal vein occlu-
sion (CRVO) and BRVO, PDR, diabetic macular edema
(DME), clinically significant macular edema (CSME),
neovascular age-related macular degeneration
(ARMD), rhegmatogenous retinal detachment (RRD),
and proliferative vitreoretinopathy (PVR).90-93
Aqueous levels of inflammatory cytokines such as IL-
6 and IL-8 increased post vitrectomy that may accel-
erate the development of cataract and glaucoma.94,95
In patients with PDR, VEGF levels significantly corre-
lated with IL-6, IL-8, and MCP-1 elevation that are
strongly correlated with each other, indicating a com-
mon pathway involved in the inflammatory process in
vitreoretinal diseases.96 In high-risk PDR, pan-retinal
photocoagulation (PRP) causes transient macular
edema as a result of increased vitreous levels of IL-6,
IL-8, and nitric oxide (NO), and RANTES (regulated
on activation, normal T cell expressed and secreted).-
97,98
In DR, vitreous levels of IL-6 play a more signifi-
cant role than in CRVO.99 In PDR, vitreous levels of IL-
4, IL-6, IL-17A, IL-21, IL-22, and TNF-α are higher than
serum and higher than epiretinal membrane (ERM) or
macular hole (MH).100 In early or late ARMD, com-
bined effects of CRP, IL-6, soluble intercellular adhe-
sion molecules-1 (sICAM-1), and plasminogen
activator inhibitor 1 (PAI-1) have been recognized.101
In ARMD, aqueous humor levels of VEGF are signifi-
cantly related to the choroidal neovascularization
(CNV) activity but the levels of IL-6 and IL-8 are sig-
nificantly correlated with the CNV size.102 Vitreous
levels of IL-6, IL-7, IL-15, Eotaxin, G-CSF, IP-10, and
RANTES are significantly increased in active and inac-
tive retinopathy of prematurity (ROP), but VEGF has
the strongest correlation with the vascular activity.103
In patients with endophthalmitis, AqH and vitreous
levels of IL-1β, IL-6, IL-17, and MIP-3alpha are
elevated.104 In Behcet’s disease and active posterior
segment involvement, serum levels of IL-6, IL-8,
TNF-α, VEGF, and malondialdehyde (MDA), and
AqH levels of IL-6, IL-8, VEGF, and MCP-1 were sig-
nificantly higher than those without active intraocular
inflammation.105 In Eales’ disease, serum and vitreous
IL-6 expression stimulates acute inflammatory and
angiogenic reactions through the modulation of CRP
and VEGF concentration.106 Often a primary central
nervous system lymphoma masquerades as uveitis. A
ratio of vitreous IL-10 to IL-6 greater than 1 and detec-
tion of heavy-chain immunoglobulin and T-cell recep-
tor gene rearrangements provide molecular diagnosis
of B- and T-cell lymphoma, respectively, with a sensi-
tivity and specificity greater than 95%.107
Ocular Immunology & Inflammation

Orbital Effects
In patients with active thyroid-associated ophthalmo-
pathy (TAO), tear IL-1β, IL-6, and IL-8 are significantly
increased and are positively associated with clinical
activity score of the disorder and the lacrimal gland
axial and coronal size.108 These factors in addition to
RANTES play a central role in orbital inflammation
and fibrosis process.109 In Graves ophthalmopathy
(GO), CD4 to CD8 ratio and secretion of IL-6, IL-10,
and TNF-α are significantly increased.110 Although in
Graves’ disease, (GD) and GO tear IL-1β, IL-6, IL-13,
IL-17A, IL-18, TNF-α, and RANTES are significantly
higher than normal and a 2.5-fold increase in IL-6
release is seen, significant positive correlation was
only found between clinical activity score and the
release of IL-6 and plasminogen activator inhibitor-1
in the GO group.111 In TAO, cluster of differentiation
(CD)-40-CD40 ligand (CD40L) produced by fibrocytes
leads to expression of several cytokines such as IL-6,
TNF-α, IL-8, MCP-1, and RANTES. CD40L inhibition
might represent a therapeutic target for TAO.112 Tear
inflammatory cytokines including IL-6 are increased
during nasolacrimal duct obstruction and remain
high until silicon tube removal.113
IL-6-TARGETED IMMUNOTHERAPY
In recent years, studies are focused on immunological-
based treatments in ocular inflammation. Each part of
the hexameric molecule of IL-6/IL-6Ralpha/gp130 sig-
naling complex may be the target for therapeutic pur-
poses such as the interaction sites between IL-6 and IL-
6Rα (site I), the D2 and D3 domains of gp130 and IL-
6/IL-6Rα (site II) which contributes to the stabilization
of the IL-6/IL-6Rα/gp130 signaling complex and
finally the D1 domain of gp130 and IL-6/IL-6Rα (site
III).114
Suppression of IL-6-related ocular inflammation via
immunological by-product manipulation has recently
been considered. For example, IL-17 or TNF in corneal
graft rejection and uveitis,115,116 IFN-β in experimental
autoimmune uveoretinitis (EAU) mediated by Th1 and
Th17 cells,117 and OSM-mediated immunotherapy in
retinitis pigmentosa (RP).118 On the other hand, mod-
ulating the activities of IL-6 and its receptor with engi-
neered synthetic protein analogs are ongoing. For
example, mAb against the IL-6 receptor
(Tocilizumab) in patients with refractory uveitis and
macular edema,119,120 TLR3 analog (polyriboinosinic-
polyribocytidylic acid (poly(I:C)) (Tranilast) for con-
trolling corneal HSV-1 infection,121,122 NF-κB inhibitor
for the treatment of ARMD,123 and PDGF-BB-neutra-
lizing antibodies in GO.124 Also synthetic immunosup-
pressive medications with direct or indirect effects on
IL-6 activities are developing such as topical
© 2017 Taylor & Francis Group, LLC
IL-6 and Ocular Inflammation 7
ophthalmic tofacitinib (a Janus kinase inhibitor) in
ocular surface inflammation,125 topical cyclosporine
to arrest KCN progression,126 topical cyclosporine,-
127,128
anti-TNF (infliximab),129 methotrexate, bevaci-
zumab, and angiogenin (ANG) (a component of tear)
for corneal neovascularization in alkali burn,130–133
intravitreal injection of methotrexate for vitreoretinal
lymphoma;134 immunotherapy with Ipilimumab and
anti-programmed death ligand-1 (PD-L1) antibodies in
uveal melanoma;135 tocilizumab, sarilumab, siruku-
mab, olokizumab, clazakizumab, and siltuximab in
VKH, Behcet, and sarcoidosis;136 Nintedanib, a FGF-
and PDGF-receptor targeting drug in GO;137 and intra-
venous Tocilizumab in intractable TAO.138
Steroids play multifunctional roles in controlling
inflammation related to IL-6. Examples of such ster-
oids are Mapracorat, a novel glucocorticoid receptor
agonist in hyperosmolar-induced dry eye syndromes;-
139
dexamethasone, tacrolimus, and hydrocortisone for
inhibition of corneal myofibroblasts and human cor-
neal epithelial cells (HCEC) activity in corneal
inflammation;140–142 intravitreal triamcinolone aceto-
nide injection for neovascularization in CRVO and
BRVO;143,144 controlled release dexamethasone deliv-
ery system in ocular burn with desiccating stress;145
and sustained-release formulation of dexamethasone
(Ozurdex) for inhibiting PVR.146 Hormones and
related proteins have inhibitory effects on proinflam-
matory cytokines such as IL-6. Examples of these hor-
mones are estrogen (17β-estradiol) in hyperosmolar
stress-induced dry eye,147 and 17β-estradiol and pro-
gesterone in PVR.148
Fatty acids are able to control IL-6-induced inflam-
mation. For example, α-linolenic acid (ALA) plays a
therapeutic role in LPS-induced dry eye,149 and ultra-
violet (UV)-B mediated corneal and conjunctival
degeneration.150 Also, alpha-melanocyte stimulating
hormone (α-MSH), a neuropeptide, controls inflamma-
tion through anti-IL-6 activity in cataract surgery.151
There are many studies on the roles of herbal
extracts and natural products in controlling the IL-6-
related inflammation. For instances, docosahexaenoic
and eicosapentaenoic acid in meibomian gland
dysfunction;152 curcumin, a natural polyphenol
extracted from turmeric in hyperosmolar dry eye
conditions;153 main polyphenol component of green
tea and medicinal plant extracts in dry eye;154,155 active
substances and extracts of aloe vera including ethanol
and ethyl acetate in ocular surface and corneal
inflammation;156 selenium (Se)-lactoferrin eye drop,
that is a component of lactoferrin that binds with
selenium instead of iron in corneal epithelial abnorm-
alities in dry eye disease;157 calcitriol (1,25-dihydroxy-
vitamin D3) in ocular surface inflammatory disorders;-
158
eicosapentaenoic acid (EPA) in endotoxin-induced
uveitis;159 high-molecular-weight hyaluronan in UVB-
induced apoptosis and inflammation;160 fatty acids,
omega-3 and -6 for protection of trabecular meshwork
8 H. Ghasemi

TABLE 1. Summary of IL-6-mediated immunotherapy in ocular inflammations.

Segments Immunologic Hormones, peptides, fatty acids Naturals Gene

Cornea; Conjunctiva Immunosuppressive Dexamethasone Curcumin LV.PD-L1

Anti-TNF-α Hydrocortisone Green tea
Anti-IL-6R Mapracorat Aloe vera
Anti-VEGF Tacrolimus Hyaluronan
poly(I:C) Estrogen Calcitriol
Monoclonal Ab. α-Linolenic acid Selenium-lactoferrin
AC; uvea IL-10 Triamcinolone EPA Anti-TNF (p55)
Anti-VEGF α-MSH Marine sponge
Monoclonal Ab. Calcitriol
Retinoic acid
Vitreous; retina OSM Dexamethasone Retinoic acid IL-10 (LacZ); siRNA
Anti-VEGF Triamcinolone
NF-κB-I

AC, anterior chamber; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor; poly(I:C), polyriboinosinic-
polyribocytidylic acid; monoclonal Ab., monoclonal antibody; OSM, oncostatin M; NF-κB-I, nuclear factor-kappa B-inhibitor; MSH,
melanocyte-stimulating hormone; EPA, eicosapentaenoic acid; LV.PD-L1, lentivirus-mediated (LV) programmed death-ligand 1 (PD-
L1); p55, a 55 kDa protein erythrocyte membrane protein; LacZ, Escherichia coli beta-galactosidase encoded gene; siRNA, small
interfering RNA.

and optic nerve head against oxidative stress–induced
apoptosis and accumulation of extracellular matrix in
glaucoma and ARMD;161,162 retinoic acid and its active
component, all-trans retinoic acid in autoimmune
uveoretinitis;163,164 callyspongia extract from a marine
sponge in autoimmune disease and acquired immune
deficiency syndrome (AIDS) ocular-related cancer and
pathologies;165 and oral calcitriol in retinal inflamma-
tory disorders.166
Gene therapy is another interesting subject in IL-6-
related inflammatory disorders. Examples of such ther-
apy are lentivirus-mediated (LV) programmed death-
ligand 1 (PD-L1) for prolongation of corneal graft sur-
vival rate,167 anti-TNF gene therapy in EAU,168 modi-
fied human IL-6 gene promoter using the reporter LacZ
or human IL-10 gene in Leber’s congenital amaurosis,169
and blocking the downstream gene expression by spe-
cific small interfering RNA (siRNA) for TLR3 and alkyl-
phosphocholine in ARMD.170 These therapeutic
interventions are summarized in Table 1 .
DISCUSSION AND CONCLUSION
IL-6 as one of the most important inflammatory cyto-
kine has been recently taken in to specific considera-
tion in many scattered research articles. These fields
and subjects are mostly focused but not limited to
ocular surface disorders especially on dry eye, corneal
pathologies, uveal disorders, vitreoretinal abnormal-
ities, such as ARMD, PVR, PDR, ROP, retinal vascular
accidents and other causes of vitreoretinal angiogen-
esis or inflammatory disorders. These extensive and
wide spectrum effects of IL-6 has encouraged the
investigators to use IL-6-targeted immunotherapy
with anti-IL-6 modulations and antibodies.171
Several functions for IL-6 have been suggested. Ocular
surface angiogenesis is harmful for the ocular tissues in
most cases. The most frequent type of angiogenic activity
in humans is pterygium.61,172 Corneal angiogenesis is seen
in many frequent pathologic disorders such as penetrating
keratoplasty or corneal foreign bodies.173 IL-6, IL-8, and
MCP-1 vitreous fluid levels are significantly elevated in
vitreoretinal diseases including DME, PDR, BRVO,
CRVO, and RRD. Elevation of VEGF was significantly
correlated with IL-6, IL-8, and MCP-1. IL-6, IL-8, and
MCP-1 were strongly correlated with each other indicat-
ing a common pathway involved in inflammatory and
ischemic processes in vitreoretinal diseases.96 Recently, a
wide range of anti-IL-6 biological preparations have
emerged such as anti-TNF-α or Rituximab and
Tocilizumab, an anti-IL-6 receptor blocking mAb or
Abatacept, and CTLA4 inhibitor fusion protein designed
to target the T cell co-stimulatory signal mediated through
the CD28-CD80/86 pathway. IL-6 as an important med-
iator has numerous immune effects, and complete block-
ade of its signaling pathways may not be desirable. In this
important clinical decision, other than possible unrespon-
siveness of some patients, there are several disadvantages
and unwanted side-effects that one should consider for
involved patients.174,175
In conclusion, IL-6 plays a dual role in the eyes. On
the one hand, it protects the ocular tissues from
unwanted infections, and on the other hand, IL-6 may
destroy and damage the delicate elements of the eyes
through unwanted neovascularization or exacerbation
of inflammation. IL-6 plays and modulates many
important roles in ocular inflammation and angiogen-
esis in conjunctiva, cornea, iris, retina, and orbit. New
treatment modalities, besides to anti-IL-6 targeting
immunotherapy, have been presented in recent years.
Such interventions should be considered only in critical
circumstances to avoid the dangers of such treatments.

Ocular Immunology & Inflammation


ACKNOWLEDGMENT
Special thanks for kind permission of Peter C.
Heinrich, Freiburg, Germany, for providing copyright
permission for all colored figures illustrated in this
article.
DECLARATION OF INTEREST
The author reports no conflicts of interest. The author
alone is responsible for the content and writing of the
paper.
FUNDING
The author would like to thank Shahed University for
providing financial and logistic support.
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