`

Review Article
Insecticidal Exposure may be the Cause of Progression of Immune
Disorders and Inflammatory Diseases through Dys-regulation of
Cytokines
Latif Ahmad1*, M Zahoor-ul-Hassan Dogar2
1
Baqai College of Veterinary Sciences, Baqai Medical University, Karachi-Pakistan..2University of Sargodha,
Sargodha-Pakistan.

ABSTRACT
Industrial revolution has dangerously increased the load of environmental or environmentally induced diseases.
Recently, the insecticides (a class of pesticides killing various insects) have become one of the most important
environmental pollutants. This Review discusses the association of insecticides, cytokines dys-regulation and the
development of immuno-regulatory disorders and chronic inflammatory conditions. In spite of abundant
reviewing and reporting of various immuno-inflammatory diseases individually, efforts lack to understand the
central pathological mechanism underlying these diseases collectively. The cytokines are extensively involved in
inter-cellular communications; they are regarded attractive markers for risk stratification or patient prognosis.
In this Review, an understanding has been generated about the role of various receptors, genes and signaling
pathways etc. in the trianglular link of cytokines, immuno-inflammatory diseases and insecticides. Such role, in a
number of instances, had been those of (1) a receptor tyrosine kinase designated as c-kit or SCF receptor and
(2) NFB, the most excellently described transcription factor. The conclusion of the Review is that insecticides
are linked with increasing susceptibility to various diseases especially any type of chronic inflammation through
cytokine dys-regulation. Moreover, insecticidal toxicity can cause deviations in certain parameters of diagnosis.
So insecticide applicators must be stressed to ensure only recommended doses and formulations of insecticides if
really necessary.

Key words: Signaling pathways, pathogenesis, NFB, laboratory tests, pesticide, diagnosis.

INTRODUCTION

Among all creatures, only humans can, scientifically,
manage self-generated challenges by building additional
cultural functions, e.g., cardiologists can generate
knowledge about how to medicate a heart patient.
However, we may not instantly be able to determine
accurately some factor(s) involved in a disease.[1]
Frequently, such unknown factor is linked to artificial
Access this article online
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DOI:
10.21276/iabcr.2016.2.3.4
Received:18.08.16| Revised:28.08.16| Accepted:01.09.16
Corresponding Author
Latif Ahmad, Baqai College of Veterinary Sciences, Baqai
Medical University, Karachi-Pakistan.
Copyright: the author(s) and publisher. IABCR is an official publication of
Ibn Sina Academy of Medieval Medicine & Sciences, registered in 2001
under Indian Trusts Act, 1882. This is an open access article distributed
under the terms of the Creative Commons Attribution Non-commercial
License, which permits unrestricted non-commercial use, distribution, and
reproduction in any medium, provided the original work is properly cited.
manoeuvring of agricultural activities, culminating in fatal
and non-fatal medical problems.[2] In recent times,
insecticides have become major pollutants of industrial
revolution, which disturb our external environment and also
manipulate the microenvironment. Our focus in this
Review is towards investigating the increased incidence of
conditions with cytokine dys-regulation during last three
decades; the same is the period of intensive farming with
frequent use of insecticides.[3]
Acute phase response follows any tissue damage;
macrophages and monocytes discharge cytokines. Systemic
responses to cytokines include homeostatic (pyrexia etc.)
and other (hematopoietic/metabolic/biochemical) changes;
any dys-regulation in them causes disease. Acute phase
response (initiated by same/similar endotoxic challenge)
might be changed at multiple levels leading to various
outcomes/conditions. Susceptibility to infectious diseases
depends on the genetic basis for cytokines, but cytokine
environment is also important factor to their functioning.[4]
Evidences of the involvement of various insecticides in

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 Ahmad L and Dogar MZH: Immune disorders and inflammatory diseases through dys-regulation of cytokines
many immune defects suggest insecticide exposure and
immune defects to be linked in a broader sense.[5,6]
Role of insecticidal toxicity in diseases: Extensive use of
insecticides in various industries, household and medicine
has caused alterations in animals e.g., endotoxin-induced
macrophage stimulation via restricting nuclear factor-
kappa-B (NFB) stimulation and de-oxyribonucleic acid
(DNA) damage.[6,7] Links of insecticides exposures had
been documented with a number of conditions e.g.,
disturbed immunity, infectious/inflammatory lesions of the
kidneys, disturbed glucose homeostasis, diabetes, asthma,
acute pancreatitis, cancers and behavioral alterations
through disturbance of cholesterol
mechanism.[3,5,8,9,10,11,12,13]
Roles of cytokines in diseases:
The cytokines in almost all animals especially mammals
(including humans) are similar except for few additional
cytokines in ruminants.[14] Proinflammatory cytokines
(especially interferon (IFN)-) evoke microbicidal capacity
1.
of macrophages (Fig. 1).
2.
3.
4.
Fig 1: Highly microbicidal macrophages (M1) are formed from
monocytes by proinflammatory cytokines (especially IFN--).
Anti-inflammatory cytokines cause immunosuppression
(M2).
i.
Contrarily, interleukin (IL)-4 and IL-13 (involved in CD4+
Th2 response) are responsible for immune response (Fig. 1)
to parasites, allergy, wound healing, and tissue
remodeling.[15] Th2 helper cells assist B cells by elaborating
IL-4, IL-5, IL-10 and IL-13. Cytokines cause viralii.
replication in diseases like dengue and human
immunodeficiency virus (HIV).[16] Cytokines from adipose
cells develop insulin resistance via NFB pathway in type-
2 diabetes mellitus (T2DM), obesity, high fat diet,
hyperglycemia, protein kinase-C (PKC) activation and
oxidative stress.[17]
Precise mechanism of cytokine dys-regulation is poorly
understood. Specific cytokines may have the principal role
in certain disease e.g., IL-13 is considered both necessary
and sufficient for asthma. A single cytokine can express
specific incorporated cellular reactions. Organized groups
of cytokines track in packs and shape intricate cytokine
networks. Changes in structure of cytokine genes confer
extensive diversity in populations and are pertinent to be
reasons of sickness. The most important proteins involved
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in signalling of cytokines are signal transducer and
activator of transcription (STAT). Lack of STAT-6 protects
from all pulmonary effects of IL-13. STAT-6 is also
expressed by many immune cells.[18]
Agriculture related diseases and cytokines:
There is lack of responsibility during application of various
chemicals in underdeveloped countries. Changed
cytokines levels with insectiticidal exposure and in many
human diseases have been reported.[3] The scholastic
investigations and applied community health are not
properly aligned due to little investment in fighting animal
diseases and zoonosis.[19] Modifications in cytokines in
various tissues of animals and humans of both sexes
through insecticide toxicity might have produced such
diseases e.g., chlordane decreases proinflammatory
cytokine IL-1 and permethrin reduces anti-inflammatory
cytokine IL-10 in fetal cord serum.[20,21] Objectives of the
present Review include:
Consider possibility of the cytokines as cause of various
immuno-inflammatory diseases,
Gather evidences of diseases of being related to both
insecticides and cytokines and
Determine new insights in cytokine- and insecticide-related
diseases/disorders
Identify and classifications of Cytokines:
Cytokines have low molecular weight and are pleiotropic
signaling glyco-proteins. They are involved extensively in
inter-cellular communications, including earliest immune
and inflammatory reactions to noxious stimuli and in the
later adaptive (specific) immune responses to microbes.
They are directed by a particular gene, but can generate
numerous distinct and apparently discrete phenotypic
effects. Controversies subsist about differentiation of
cytokines and hormones, but some features have been
defined.
Concentrations of protein hormones are measured in
nanomolar (10-9); their level can change within 1/10th to
10 times only. Contrarily, cytokines are measured in
picomolar (10-12) concentrations changing about thousand
fold in disease.
Almost every nucleated cell can effectively make most
cytokines. Contrarily, certain distinct glandular structures
can only produce typical hormones.[22]
There is no unanimous classification of cytokines. Both
functional and structural groups of cytokines have been
explained below to help readers understand this Review
easily.
Functional Types of Cytokines:
Seven well-known groups of cytokines on the basis of
functions have been discussed.[23]
Interleukins
ILs include numerous related proteins, formed by Th
lymphocytes (particularly Th1 cells), cytotoxic T
lymphocytes (TC cells) and natural killer (NK) cells.[24] ILs
intercommunicate WBCs, administer immune responses,
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 Ahmad L and Dogar MZH: Immune disorders and inflammatory diseases through dys-regulation of cytokines
induce growth of lymphoid and primitive hematopoietic
stem cells and instruct other cells to divide and
differentiate.[25]
Lymphokines
T-lymphocytes secrete many cytokines grouped together as
lymphokines, which play regulatory function in immune
disturbances and coordinate inflammation. In a specific
disease, disturbance in one subset of T-cells or the other
may explain the disease mechanism.[26,27] Immature Th
subset (Th0) produces lymphokines related to both Th. Th1
and Th2 cytokines inhibit functions of each other. Specific
transcription factors regulate Th cells: T-bet for Th1 cells,
GATA3 for Th2 cells, Retinoic acid orphan receptor-t
(RORt) for Th17 cells, and FOXP3 for Tregs.[27]
Th1 cells produce IL-2, IFN- and TNF-, which all resist
intracellular pathogens, promote cell mediated immunity
and produce opsonizing antibodies; many activated
macrophages may contribute in this immunological
function.[27] Th1 cells are the principal CD4+T-cells, and
Tc1 cells the principal CD8+T-cells presented in COPD-
lungs.[28] IFN- is the leading cytokine formed by Th1 and
Tc1 cells and is important in COPD-inflammation by
inducing chemokines, but its level is reduced in any type of
asthma except very severe disease and acute
exacerbations.[26] The cytokines produced by Th2 cells are
involved in various immunological functions (Table 1).
GATA transcriptor factors have unique skill to attach the
Table 1: Th2 Cytokines and their functions
S immunity and regulatory signals of the cell growth has
Cytokine Function (s)/disease(s)
# been described e.g., lack of epithelial growth factor
Delayed-type hypersensitivity, IgE
1 IL-4 Production, Alterations of pulmonary
air-spaces.[29]
Tc cell activation, Eosinophils-
2 IL-5
mediated inflammation.[27]
3 IL-6 Supports Th1 and Th17 responses.[29]
Inflammation, allergy and tumor
4 IL-9 immunity Increased IL-9 level
provokes asthma.[30]
Inhibit Th1 cytokine synthesis,
5 IL-10
Inhibit antigen-presenting cells.[29]
Production of IgE, Morphological
alterations of pulmonary air-spaces,
6 IL-13
Pleiotropic in action Asthma and
allergy.[27,29]
DNA sequence GATA. GATA-3 participates in nearly all
stages of T-cell growth (from common lymphoid
progenitor to Th2), and also plays roles beyond immune
system.[7] Th17 cells differentiate under the influence of
TGF-, IL-6, IL-21 and IL-23 by Th17-motivating
cytokines.[27]
Proinflammatory/inflammatory cytokines:
Their up-regulation triggers development of several
inflammatory diseases. Several infectious diseases can
stimulate upregulation of inflammatory cytokines. Acute
inflammatory cytokines include IL-1, TNF-, IL-6, IL-11,
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IL-8 and other chemokines, granulocyte-colony stimulating
factor (G-CSF) and granulocyte macrophage (GM)-CSF.
In vitro studies on human keratinocytes revealed the
insecticide monocrotophos to significantly increase nitric
oxide, lactate dehydrogenase, malanodialdehyde, nuclear
changes, pro-inflammatory cytokines (TNF-, IL-6 and IL-
8) and reactive oxygen species generation.[31]
Chronic inflammatory cytokines are grouped as: humoral
(IL-4, IL-5, IL-7 and IL-13) and cellular (IL-1, IL-2, IL-3,
IL-4, IL-7, IL-9, IL-10, IL-12, IFNs, TGF-, and TNF-).
Under influence of IL-12, NK cells, macrophages and T
cells are motivated to form IFN-. IL-12 is essential to
stimulate inflammatory cytokines of Th1 type which induce
IFN- in immunity.[4] IL-6 coordinates other cytokines and
creates an association between non-specific and adaptive
immune systems. IL-6 is among causative factors in insulin
resistance, T2DM and pulmonary damage in allergic
asthma.[18] The level of IL-6 and IFN- in the bronchi after
experimental viral infection had been lowered in progeny
mice receiving insecticide methamidophos.[32]
Growth Factors (GFs):
Produced by leukocytes and structural cells, GFs promote
continued cellular existence. GFs cause morphological
modifications in airways; transforming GF-beta (TGF-)
and fibroblast GFs (FGFs) motivate fibroblast propagation
(fibrosis). Other GFs include: regulatory T cells (Tregs),
TGF-, GM-CSF, stem cell factor (SCF)/c-kit-ligand/steel
factor, neurotrophins, EGF and vascular endothelial growth
factor (VEGF). Association amid antiviral non-specific
receptor (EGFR) or use of EGFR results in more viral
replication and impairment of antiviral genes.[33] Unusual
expression or utility of SCF/KL had been reported in
numerous diseases. Insecticides (e.g., pyrifluquinazon)
perturb c-Kit pathways via PI3-kinase/Akt signalling
pathway, the protein-rich tyrosine kinase-2 (Pyk2) and the
c-Myc.[3,4,34]
Chemokines (Chemoattractant/Chemotactic
Cytokines):
They are chemotactic for inflammatory cells and have
diverse target cell specificity. Inflammatory cells
themselves or lung parenchymal cells can produce
chemokines. Chemokines may be either homeostatic, or
inflammatory, or both. They play important roles during
zygote development, embryogenesis, lymphopoeisis,
myelopoiesis, hematopoiesis and cardiac and
[35]
musculoskeletal development. Many diseases emerge
through un-controlled chemokines and chemokine
receptors.[35] Any acute injury or infection triggers WBCs
to the site, for which the role of chemokine (e.g., IL-8 and
CXCR) is necessary (Fig. 2).
Exposures to organochlorine insecticides altered these
leukocyte-related immune functions through inhibition of
IL-8 and CCL5 in monkeys.[36]
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 Ahmad L and Dogar MZH: Immune disorders and inflammatory diseases through dys-regulation of cytokines
Figure 2: Upon infection, epithelial cells stimulate
chemokines (IL8, CCL5 etc.) which recruit WBCs there.
Inflammation sets in with secretion of more cytokines and
mediators. Damaged epithelial cells are shed, which along
with other debris may cause obstruction of passages.
Chemokines have four families.
1. CC family of chemokine has CCR2 (CC chemokine
receptor type 2), CCR3, CCR4, CCR8 and CCR5 as
important members. The monocytes and T-
lymphocytes stimulate CCR2 by chemokine (C-C
motif) ligand 2 (CCL2/monocyte chemotactic protein-
1). Principally, the eosinophils perform expression of
CCR3, involved in chemotactic reaction to many
chemokines.[36] Intravascular adherence and
transmigration of neutrophils are guided by CC motif
chemokine CCL3 and canonical neutrophil
attractants. [37]
Activation of CCR5 occurs by CCL3,
CCL4 and CCL5; all of these and CCL2 are up-
regulated in COPD patients. The expression of CCR5
is raised in airways of asthma patients and in COPD
patients, suggesting its role in recruiting T
lymphocytes, macrophages and eosinophils.[38] CCR5
and CXCR4 had been especially regarded essential to
serve coreceptors during HIV entry; HIV established in
vaginal and rectal mucosa had been principally
reported to be CCR5-dependent.[35]
2. CX family of chemokine: The expressin of CXCR2
(and CXCR1) occurs mostly by neutrophils and
occasionally by eosinophils, mast cells, T
lymphocytes, basophils, endothelial, hepatic, renal and
neuronal cells. The CXCR2 receptors get activated by
seven morphologically similar chemokines (CXCL1,
CXCL2, CXCL3, CXCL6, and CXCL8).[39] CXCL1
and CXCL8 concentrations are strikingly raised in
induced sputum of patients with COPD and asthma
exacerbations and draw a parallel with the higher ratio
of neutrophils.[36] CXCL8 and CXCL5 show additional
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rise during exacerbations of COPD; CXCL8 is also
increased in the airways and sputum with severe
asthma.[26] The CXCR3 is highly expressed by T cells
in the peripheral airways of COPD sufferers.[28]
CXCR3 is stimulated by CXCL9, CXCL10, and
CXCL11, they all are provoked by IFN- and are
related to COPD severity.[39] CXCR4 receptors are
expressed on Th2 cells and stimulated by CXCL12; the
homeostasis depends mainly on rigid control of these
cytokines.[24] CXC chemokine ligand-4 (CXCL4)
synchronizes communication of platelets with
monocytes in acute inflammation and when CC
chemokine becomes available, monocytes attack the
inflamed site.[39]
3. XC family of chemokines includes lymphotactins i.e.,
XCL1 (lymphotactin-) and XCL2 (lymphotactin-).
They engage NK and T cells, have only one disulfide
bond and heterogenesity in structure.[40]
4. CX3 family of chemokine has CX3CL1 or CDF
(chemical domain of fractalkine) as the exclusive
member formed by airway epithelium after activation
with IFN-, TNF- and IL-1.[40]
Anti-inflammatory cytokines
They depressingly adjust inflammatory reaction e.g., IL-12
stimulates Th1 cells to discharge IFN-, which may repress
Th2 cytokines and allergic inflammation. TGF- slows
down CD4+ T cells, thus helping immuno-modulation. IL-
10 is formed by Tregs and macrophages; it reduces the
creation of several proteins (MMP-9 etc.) and numerous
pro-inflammatory cytokines.[27]
TNF family
TNF is key activator of inflammation. TNF- is secreted by
many cells (e.g., macrophages, mast cells, T cells, airway
smooth muscle cells and epithelial cells). TNF is highly
poisonous. Almost every animal cell exhibits receptors for
TNF.[25] TNFR-1 is the major cell surface receptor for TNF
on hepatocytes. Activation of death domain in TNFR1
causes apoptosis; other pathways can be defending; they
may activate NFB, protein kinase activated by mitogen, or
STAT pathways. NFB and STAT pathways are disturbed
with insecticide toxicity.[3]
Macrophage Migration Inhibitory Factor (MIF):
MIF is an essential effector molecule of immunity and
neuro-endocrine alignment. MIF stimulates pleiotropic
tasks in inflammation, malignancies/cancers, metabolic and
endocrine activities. MIF is also expressed by epithelial
cells. Epithelial dysplasia has been reported as consistent
lesion in Wistar rats exposed concurrently to ultra-voilet
rays and organophosphate (OP) insecticides.[41]
Structural Types of Cytokines:
The cytokines can be divided into four types on the basis of
structure.[23]
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IFNs:
IFN was formerly recognized as a factor which interferes
viral replication in vitro. On the basis of type-specific
receptors, IFNs have three types:
i. IFN-, IFN- etc. are required for immunity against
most viruses.
ii. IFN- acts like factor activating macrophages; essential
agaisnt bacteria, fungi, parasites etc.
iii. IFN- is further divided: IFN-1 (IL-29), IFN-2 (IL-
28A) and IFN-3 (IL-28B).[42]
Helical Cytokines
Growth hormone (GH), erythropoietin (EPO) and prolactin
(PRL) are helical cytokines. They have two receptor
binding sites: site 1 (high affinity) and site 2 (low affinity);
every receptor has two domains (intracellular and
extracellular) joined through transmembrane helix. When
the two sites on a helical cytokine get occupied by two
receptor molecules, the receptor in that cytokine is
activated leading to transphosphorylation of two Janus
kinase-2 (JAK2) molecules. The phosphorylation of the
JAK2 molecules is followed by downstream signaling.[43]
GH axis can adjust inflammatory progression according to
needs, support cell cycle successions of lymphoid tissue
and check apoptosis through NFB and
phosphatidylinositol 3 (PI3)-kinase/Akt pathway.[20] EPO
is formed by fully-developed kidneys. EPO is induced by
low blood O2 through the transcription factors. EPO
increses RBCs and plays several roles exterior to bone
marrow including erythropoiesis, tissue protection and
restricting apoptosis.[44] PRL, a pituitary hormone with very
important responsibility in reproduction, can also perform
like a cytokine concerned with the immune reactions. In its
presence, immune cells propagate fast and synthesize more
cytokines through several intracellular pathways (e.g.,
Jak2/STAT, Ras/Raf/MAPK). The life-cycle and capacity
to form pathogenic autoantibodies of autoreactive B-
lymphocytes is extended by PRL in systemic lupus
erythematosis.[45]
IL-2:
IL-2 shows pleiotropy; it forces the T-cells to grow, boosts
up NK cells, stimulates proliferation of regulatory T cells
and is involved in cell death induced through receptor
activation. IL-2 may prime/sustain/develop Th1 and Th2
segregation; while it inhibits Th17 segregation but can also
develop Th17 cells.[46] Insecticides reduce the skill of
well-purified human NK cells to lyse tumor cells through
imbalancing NK-inhibitory (IL-4) and NK-stimulatory (IL-
2, IL-12 and/or IL-10) ILs. Some insecticides bring out
concordant signaling pathways (e.g., JAK-STAT) in the
mouse models having common characteristics with some
pathways detected in human Parkinsons disease;
Parkinsons type neurodegeneration had also been reported
in insecticide-exposed rural peoples.[47]
IL-10 Subfamilies of Cytokines:
They include IL-10, also called cytokine synthesis
inhibitory factor (CSIF), cytokines resembling IL-10 (IL-
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19, IL-20, IL-22, IL-24 and IL-26) and type-III IFNs (IL-
28A, IL-28B and IL-29), which less distinctly resemble IL-
10. IL-10 family cytokines are critical to epithelium
homeostasis; they contribute in several infectious and
inflammatory diseases.[48] TNF- and IL-10 are involved in
tuberculosis (TB). Certain single nucleotide polymorphisms
(SNPs) within the promoter region of the IL-10 and TNF
genes have been associated with altered levels of
circulating IL-10 and TNF-. IL-10-1082, IL-10--819, IL-
10--592 alleles or haplotypes containing these alleles may
influence the balance of pro- and anti- inflammatory
cytokines and consequently contribute in TB
susceptibility.[49] Similarly, a negative association of IL-10-
1082GA and positive relationship of IL-10-1082GG and
IL-6-174GC promoter region polymorphism with coronary
artery disease (CAD) in Pakistani population suggests that
upset in the Th1/Th2 balance may manipulate the
vulnerability of CAD.[50] Insecticides (e.g., permethrin) had
been negatively linked with IL-10, indicating their role in
susceptibility to TB and CAD.[21]
Diagnostic tests versus diseases, Cytokines and
Insecticides:
Diagnostic laboratory tests can assess the inflammatory
response, various cytokines and cytokine-related diseases;
insecticide toxicity may doubt their results. In the following
paragraphs, hemoglobin (Hb), erythrocyte sedimentation
rate (ESR), c-reactive proteins (CRP), leukocytes,
pancreatic functions, liver function tests (LFTs), kidney
function tests (KFTs), blood glucose and various hormones
have been discussed in the respective scenario.
Hb:
Cytokines in chronic inflammatory conditions mediate
immune processes leading to hypoferremia leaving
microbes without iron, but by some faults iron-restricted
erythropoiesis and anemia may result. In mature non-
diabetic peoples, increased danger of diabetes and more
robustly the danger of heart disease and mortality had been
linked with glycated Hb (HbA1c) relative to fasting
glucose. Low Hb concentrations had been linked with
disease severity of rheumatoid arthritis (RA) etc.[51] The
anemia development, decreased Hb and mean corpuscular
Hb concentrations had also been suggested in insecticide
toxicity studies.[52]
ESR, CRP and Red Cell Distribution Width (RDW):
Combination of ESR and CRP readings at 24 hours
forecasts RA susceptibility and severe acute pancreatitis
(SAP) accurately; TB and diabetes are also linked with
them.[53] Standard range of ESR had been reported in most
dengue patients at any stage, differentiating it from
bacterial diseases.[54] ESR is a vital indicator of active
ulcerative colitis (UC) and RDW is a sensitive and specific
indicator for verifying active Crohns disease (CD).[55]
High RDW is an autonomous feature associated with fatal
heart failure in aged persons. Reduced RDW is noted in
multiple sclerosis, melancholy and hypertension.[56] Serum
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 Ahmad L and Dogar MZH: Immune disorders and inflammatory diseases through dys-regulation of cytokines
CRP levels were raised 3-5 fold, while RDW lowered in
insecticide sprayers.[57,58] ESR increased following both
acute and sub-acute exposure of chlorpyrifos insecticide in
fish.[59]
Leukocytes:
Basic module of innate immunity is neutrophils relocation
into inflamed tissues; blood neutrophils undergo polarized
movement from first to last endothelial cells (ECs) coating
the venular lumen in a luminal-to-abluminal route. During
this transendothelial migration, enzymes convert
lysophosphatidylcholine (LPC) to lysophosphatidic acid.
Neuropathy target esterase (NTE) hydrolyzes LPC in
vitro.[60] NTE is a secondary target of some insecticides;
insecticides damage the leukocyte functioning by attacking
NTE and favouring cytotoxic accumulation of LPC to
rupture ECs.[61]
Proteins:
Insecticides may attach to albumin, lipoproteins and to
alpha-1-acid glycoproteins (AGP). AGP determinations are
considered diagnostic for inflammatory bowel disease
(IBD) and CD.[12] The mitochondrial translocator protein
(TSPO) has enormous attraction to bind with drugs and
cholesterol and is highly expressed in colon cancers and
also in initial inflammation in IBD. The mixture of TSPO,
voltage-dependent anion channel and adenine nucleotide
transporter binds various pollutants including
insecticides.[62] The evaluation of IBD in dogs through
canine IBD activity index (CIBDAI) is insufficient to
predict disease status, so combination of CIBDAI,
histologic score, and serum albumin level is used for
sufficient curative strategies. Albumin is an essential
parameter for dietary management of chronic pancreatitis
and scrutinizing diabetic pathophysiology.[63] Globulin is
also involved in some diseases e.g., group-specific
component globulin, Gc-globulin is a prognostic and
treatment marker in SAP.[21,64] Deviation in serum albumin
and globulin concentrations and their structural and
functional features resulting from insecticidal
treatment/exposure may lead to misdiagnosis and/or
mismanagement and/or exaggeration of these conditions.[6]
Insecticides slow down calcium recruitment in G-protein-
coupled receptor (GPCR) leading to GPCR desensitization
and internalization through stimulation of conventional
PKC.[65]
Blood Glucose:
Acute hyperglycemia exaggerates hyperinsulinemia and
upregulates circulating cytokines.[66] Impaired glucose
tolerance (IGT) in sepsis is linked with alterations in
plasma glucagons and cortisol and inflammatory cytokines
(IL-6 and TNF-); it is beacuse IGT builds up acute
hyperglycemia through glucose infusion.[51] Expressions of
all glucose-6-phosphate isomerase-derived indicators in RA
are elevated. Insecticides break glucose homeostasis,
stimulate momentous pancreatic injury and cause oxidative
damage to pancreas.[10] The suggested mechanism involves
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stimulation of adrenergic receptors (AR); it includes
hyperlactacidemia through -AR and lactate consumption
and hyperglycemia through -AR.[66]
LFTs:
Hepatic dysfunction had been described in children with
serologically confirmed dengue infection; its severity in
dengue hemorrhagic fever and DSS (dengue shock
syndrome) patients is more than that in dengue fever
patients. Similarly, liver dysfunction is extremely frequent
in all types of dengue infectivity in adults, with aspartate
transaminase (AST) ascending drastically higher than
alanine tranaminase (ALT). Serum levels of bilirubin, ALT
and alkaline phosphatase are significantly raised in long-
suffering peoples with DSS, haemorrhage and sequential
infection.[54] The insecticides also lead to elevated
transaminases.[6]
T2DM also deviates the LFTs, including reciprocal
alterations in two endoplasmic reticulum enzymes (hexose-
6-phosphate dehydrogenase and isocitrate dehydrogenase);
these enzymes produce NADPH and determine the
directional activity of hepatic 11-hydroxysteroid
dehydrogenase (11-HSD1).[67] Several insecticides utilize
carbonyl moieties in their mechanism of activity; carbonyl
reductase in liver microsomes is chiefly credited to 11-
HSD1.[68] Subtle chronic rises of transaminases regularly
had been considered a sign of causal insulin resistance, it is
notably true for ALT and especially in Asian populations.[6]
The link of insecticides toxicity (e.g., imidacloprid) and
life-threatening multi-organ dysfunctions may create
diagnostic difficulties in such patients after contact with
insecticides.[69]
Pancreatic Function Tests:
The initial stage acute pancreatitis is detected more clearly
by IL-8 serum levels than those of CRP and TNF- to
differentiate it from high-risk patients with severe
disease.[25,54] Proton pump inhibitors (PPIs) can recover
glucose dysregulation and stimulate pancreatic beta-cell
neogenesis in T2DM. PPIs undergo metabolism through
cytochrome P450 system and insecticides decrease
cytochrome P450 17-hydroxysteroid dehydrogenase
(P450 17).[3,70]
KFTs:
T2DM patients are under greater threat to chronic kidney
problems, which in turn cause heart related deaths.
Balanced activation of peroxisome proliferator-activated
receptors (PPARs) i.e., PPAR and PPAR in diabetics can
improve insulin sensitivity.[71] A 3-hydroxy, 3-methyl
glutaryl coenzyme A (HMG-CoA) reductase inhibitor
atorvastatin is included in sub-network of PPAR. Some
insecticides prospectively modulate the course of PPAR
signaling and HMG-CoA reductase.[3] Tamm-Horsfall
protein (THP) had been assumed to perform regulatory
function of renal and systemic immunity manipulating
cytokine excretion.[72] Insecticides when acting on renal
tubules diminish secretion of THP.[73]
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 Ahmad L and Dogar MZH: Immune disorders and inflammatory diseases through dys-regulation of cytokines
Hormones: The rise of cortisol concentration in T2DM is
un-accompanied by adrenocorticotrophic hormone fall,
which verifies essential fault in hypothalamic-pituitary-
adrenal (HPA) axis. Cytokines influence the neuro-
endocrine processes in all stages of reproduction; elevated
plasma/serum LH in insecticide exposed male subjects
occur due to normal negative feedback in response to the
decreased testosterone hormone of the HPA.[74] Impaired
insulin and glucose metabolisms had been connected with
many diseases (e.g., CD, TB and RA), in addition to
diabetes.[15] Insecticides reduce glucose oxidase activity
and deteriorate glucose tolerance in animals and also
disturb neurotransmitter or ion channel systems.[66] Vitamin
D upregulates mitogen-activated protein kinase
phosphatase-1, reduces lipopolysaccharide (LPS)-induced
p38 stimulation and prevents monocytes/macrophages from
synthesis of several cytokines.[60] Insecticides had been
linked with vitamin D deficiency in humans and thin avian
egg shells, strongly connected to Ca+2 metabolisms
(controlled by estradiol and vitamin D).[75]
How Cytokines dys-regulate?
Inflammation sets in when innate immune cells perceive an
insult and cytokines are stimulated. Fig. 3 depicts normal
functioning of cytokines. Supervision of the inflammatory
process involves pattern recognition receptors (PRRs);
nearly all PRRs take action to pathogen-associated
molecular patterns thropugh various transcription factors
e.g., NFB.[20] NFB gets activated in any oxidative stress.
Differences within cytokine genes have been associated
with diversity within individuals in their immune response
and in resistance to multiple pathogens. [76]
Figure 3: Normal functioning of cytokines
During cellular responses of acute inflammation,
chemokines are expressed as attached to proteoglycans.
WBCs get stimulated and receptor avidity of integrins gets
enhanced, so that additional integrins attach to proper
ligands on WBCs and bunch together. During vascular
reactions in acute inflammation, cytokines lead to a
sluggish and delayed withdrawal of endolthelial cells;
cytokines support appearance of selectins and integrin
ligands.[77] The enhanced integrin avidity and enhanced
appearance of integrin ligands at the inflammatory sites
consequently lead to firm binding of WBCs to
endothelium. In the presence of products of bacteria (e.g.,
endotoxins, LPS), activated macrophages, endothelial cells
www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3
and mast cells secrete TNF and IL-1. TNF enhances
endothelial thrombogenecity and stimulates neutrophils;
IL-1 stimulates tissue fibroblasts leading to extra-cellular
matrix (ECM) accumulation.[78] Both TNF and IL-1 can be
presented at far-off sites via blood to bring the systemic
acute phase reaction and can also operate as endogenous
pyrogens, raising the concentration of cyclo-oxygenase to
facilitate conversion of amino acid into prostaglandins
(PGs). In the hypothalamus, PGs (particularly PG-2)
motivate formation of neurotransmitters, which function to
retune the body temperature scale at an upper point. Acute
phase proteins (several hundred times than normal) are
expressed by the liver in systemic inflammation.[79] The
most excellently recognized acute phase proteins (i.e.,
CRP, fibrinogen and SAA) are up-regulated by cytokines
(particularly IL-6). Fibrinogen attaches to red corpuscles
leading to rouleaux formation; ESR is an easy experiment
for the systemic inflammation.[80]
Depending upon the stimulus, inflammatory responses can
be initiated by any of PRRs (Toll-like receptors, receptor
for advanced glycation end products, and scavenger
receptors). Ligation of a PRR stimulates signal transduction
pathways and control of various transcriptional and post-
transcriptional molecules (i.e., constituents of NFB, IFN
regulator factor families and activator protein-1); pro-
inflammatory target genes are adjusted encoding cytokines,
enzymes, and other molecules necessary for pathogen
removal.[20] During a chronic inflammation, some cytokines
(especially IFN-, IL-12) contribute the key role.
Macrophages having longest half-lives carry out most
efficient phagocytosis than other cells (lymphocytes,
monocytes, eosinophils, plasma cells and mast cells).[20]
Macrophages get activated by various activation signals
e.g., cytokines, other inflammatory mediators, ECM
proteins and different microbial products.[15] In chronic
inflammation, macrophages accrue and propagate instead
of dying off into lymphatics. The cytokines sequester the
lymphocytes in lymph-nodes so that leucopenia follows
bacterial, viral, rickettsial and protozoal diseases. Both B
and T-cells can travel into inflammatory sites by means of
various adhesion molecules and chemokines and engage
other WBCs.[78] Balanced discharge of various cytokines is
essential for recruiting macrophages in inflammatory sites.
IFN- is capable of motivating macrophages to combine
into giant cells. Macrophages present antigens to T-cells,
express membranous molecules (i.e., co-stimulants) and
secrete cytokines (particularly IL-12) that excite T-cell
responses; again cytokines are produced (e.g., IFN-). The
mucosal dendritic cells and mononuclear phagocytes
maintain the stability of resistance to pathogens and
acceptance to antigens resulting from bacterial flora and
food. This stability is synchronized by both cellular
communications and the discharge of cytokines. An
example of dysregulated cytokines functioning has been
presented in Fig. 4. Various diseases occur due to improper
and persistent activation/polarization of immune cells
leading to tissue damage.[15] The insecticides frequently
produce reactive oxygen species which cause cellular
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 Ahmad L and Dogar MZH: Immune disorders and inflammatory diseases through dys-regulation of cytokines
damage via lipid peroxidation, motivation of NFB,
mitochondrial injury and apoptosis in different tissues
resulting in various (pulmonary, renal, hepatic, endocrine,
neuronal) consequences.[3,6]
Figure 4: A simple example of dysregulated cytokines /
Cytokine dysregulation in autoimmunity
SUMMARY
Specific cytokines or their receptors are tremendously
important in many diseases. But stopping the cytokines
involved causes immunosuppression. Consequently,
additional strategies for precautionary and restorative
measures are required e.g., discovering the factors initiating
or favouring such diseases. There is variation of cytokine
genes within species and individuals; such population
variation may be reduced within similar work force.
Therefore this Review had addressed various studies
carried out in humans working in agricultural set-up or
experimental and domestic animals exposed to various
insecticides. A number of signalling pathways, genes,
transcription factors and receptors have been implicated in
insecticidal poisoning, which are also key players in
cytokine functioning. JAK-STAT pathways are the most
important pathways involved in signalling of cytokines;
they are stimulated when SCF binds to c-kit. The same
process is involved for some other pathways e.g., PI3-
kinase, PLC-, Src kinase and MAP-kinase pathways. The
insecticides can perturb c-Kit pathways. The amendments
persuaded by many insecticides had been reported to be
correlated with modifications of the PI3-kinase/Akt
signalling pathway, Pyk2 and the c-Myc. These pathways
balance self-renewal and proliferation of haematopoietic
stem cells. The harmful effects due to insecticide exposure
include interruption in diagnosis of various immuno-
regulatory diseases and chronic inflammatory conditions,
increased risk of such diseases in those populations,
aggravation of complications following these diseases and
reduced life span of non-target exposed subjects. Such
harmful effects are mostly through the cytokines
dysregulation in the insecticide-exposed individuals.
www.iabcr.org International Archives of BioMedical and Clinical Research | July-Sept 2016 | Vol 2 | Issue 3
Further clinical and experimental investigations are needed
to give details of mechanisms involved in these alterations.
METHODS OF EVALUATIONS
This study is a multidepartment and multiprofessional joint
venture. Various studies referred in the Review are those
carried out on insecticide sprayers and patients of
tuberculosis, dengue, diabetes, RA, UC, CD, pancreatitis
etc., with description of cytokines involvement. Various
cytokines have been reviewed for related information. The
inflammatory or acute phase response can also be assessed
by diagnostic laboratory tests. So, Hb, ESR, CRP and
leukocytes have been included to know the respective link.
Acute phase responses stimulate down-regulation of
albumin production and decreases total proteins and
albumin:globulin ratio. So these proteins along with the
LFTs, pancreatic function tests, KFTs, blood glucose and
various hormones have been discussed in the respective
scenario. The parameters having some link with cytokine
related disease(s) and relevance to the insecticide exposure
have been indicated. The selection criteria in the
description had been to search in the Google Search Engine
with key words of the disease name, the diagnostic
laboratory tests and sorting research articles from the
current decade and if not available then for older ones. The
articles having linked the disease and cytokines were
regarded the favourite ones for inclusion in the description.
Similarly the material about insecticide poisoning in the
relevance to particular disease and particular parameter of
interest under review were also searched, sorted and
described appropriately.
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Source of Support: Nil, Conflict of Interest: None
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