{"id":29855,"date":"2019-12-28T10:02:06","date_gmt":"2019-12-28T10:02:06","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=29855"},"modified":"2020-04-22T07:37:35","modified_gmt":"2020-04-22T07:37:35","slug":"estimation-of-some-interleukins-in-cerebrospinal-fluid-in-children-with-meningitis","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol12no4\/estimation-of-some-interleukins-in-cerebrospinal-fluid-in-children-with-meningitis\/","title":{"rendered":"Estimation of Some Interleukins in Cerebrospinal Fluid in Children with Meningitis"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Central nervous system(CNS) cytokine production may lead to protection or damage of neural cells, depending on the specific cytokine, timing of its production, and the amount produced. Production of pro-inflammatory cytokines by microglia can induce neuronal damage or death,\u00a0 but the effects of pro-inflammatory cytokines may be modulated by production of anti-inflammatory cytokines, or by other proinflammatory cytokines. Disruption of BBB in meningitis cytokines and chemokines could cross the BBB in an area of breakdown and affect brain tissue directly, and stimulate cytokine and chemokine production by microglial cells and astrocytes(1)<\/sup>. Cytokines are small polypeptides with a wide range of inflammatory ,metabolic and immunomodulatory properties(2,3)<\/sup>.There is differ\u00adent types of cytokines including interleukin. Studies have indicated the pathological role of interleukins in both pe\u00adripheral and CNS diseases such as shock, meningitis and head injury(4)<\/sup>.<\/p>\n

The present study aimed at analyzing cytokine profiles(IL-6 , IL-1 , IL-10, IL-8),TNF-\u03b1, and CRP among patients with meningitis in comparison with healthy controls.<\/p>\n

Material and Methods<\/strong><\/p>\n

A prospective hospital based study was done during a period of one year ( from 1st.March \/ 2017 to 1st.April 2018). All patients from one month to 7.5 years admitted to the Salahalddin Teaching Hospital in Tikrit, and Pediatric Hospital in Kirkuk, Iraq with a presumptive diagnosis of meningitis were included in the study.<\/p>\n

The fluid was withdrawn by lumbar puncture, using a spinal needle No.20).The patient lies on a hard bench, taking the lateral reclined position and the needle is gently placed above or beneath the forth lumber vertebra. The amount of withdrawn C.S.F is not fixed, but usually in the range of (1-3) ml. The CSF was examined grossly for appearance and color .Freshly collected specimens were stored at 4C\u00b0.Turbid specimens were centrifuged at 3000 rpm for 10 minutes before storage. The biochemical parameters such as IL-6 , IL-1 , IL-10, IL-8 , CRP, and TNF were measured by using the commercial enzyme-linked immunosorbent assay (ELISA) kits.<\/p>\n

The C.S.F samples were divided into two groups. Normal control group , this group comprises 26 healthy individuals, and meningitis group which they were classified into four groups\u00a0 (N= \u00a026 patients)<\/p>\n

Statistical analysis<\/strong><\/p>\n

The statistical package for social science (SPSS version 21 for Windows\u00ae Microsoft, USA) was used for data analysis. Comparison between patients and controls was made using the t-test for quantitative data and \u03c72 -test for qualitative data. P < 0.05 was considered statistically significant.<\/p>\n

Results<\/strong><\/p>\n

Table 1: Demographic characteristic of study population.<\/strong><\/p>\n\n\n\n\n\n\n\n
No. of patients<\/strong><\/td>\nDiagnosis<\/strong><\/td>\n<\/tr>\n
control<\/strong><\/td>\nTuberculous meningitis<\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

Bacterial meningitis<\/strong><\/p>\n

\u00a0<\/strong><\/td>\n

Viral meningitis<\/strong><\/td>\nPartial treated meningitis<\/strong><\/td>\n<\/tr>\n
Male<\/td>\n15<\/td>\n4<\/td>\n6<\/td>\n8<\/td>\n1<\/td>\n<\/tr>\n
Female<\/td>\n13<\/td>\n3<\/td>\n3<\/td>\n6<\/td>\n4<\/td>\n<\/tr>\n
Total<\/td>\n28<\/td>\n7<\/td>\n9<\/td>\n14<\/td>\n5<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

The results of table(2)indicate the mean serum of Total protein,\u00a0 interleukine-6, IL-1 , IL-8, and, CRP, and TNF-\u03b1 , IL-10 levels was higher in patients with (63.05 \u00b1 8.08 g\/l), (0.487 \u00b1 0.184 ng\/mL),( 11.25 \u00b1 1.10 pg\/ml), (1.12 \u00b12.80 ng\/mL), (5.532 \u00b1\u00a0 0.566 mg\/dl) and (57\u00b1142 pg\/ml), (70\u00a0 \u00b1 176) respectively than in controls (25.80 \u00b14.30 g\/l), (0.1635\u00b10.0340 ng\/mL\u00a0 ),( 6.450 \u00b1 0.887 pg\/ml), (0.135 \u00b1 0.339 ng\/mL ) (1.940 \u00b1 0.227 mg\/dl ), and (5.8\u00b1 14.5 pg\/ml) , (0.1635\u00b10.0340), and (24.3 \u00b1 60.7) respectively. Also the results show that there is a significant decrease in serum Glucose level in patients(33.1\u00b1 82.8 mg\/dl)) comparing with control group (120 \u00b1 300 mg\/dl) .<\/p>\n

Table 2: Biochemical parameters of patients and the controls.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
Parameter<\/strong>s<\/strong><\/p>\n

Control<\/strong><\/p>\n

Mean \u00b1 SD<\/strong><\/td>\n

<\/td>\nPatients<\/strong><\/p>\n

Mean \u00b1 SD<\/strong><\/td>\n<\/tr>\n

Glucose <\/strong>(mg\/dl)<\/strong><\/td>\n120 \u00b1 300<\/td>\n33.1 \u00b1 82.8 *<\/td>\n<\/tr>\n
Total protein (g\/l)<\/strong><\/td>\n25.80 \u00b14.30<\/td>\n63.05 \u00b1 8.08 **<\/td>\n<\/tr>\n
Interleukine-6(ng\/mL)<\/strong><\/td>\n0.1635\u00b10.0340<\/td>\n0.487 \u00b1 0.184**<\/td>\n<\/tr>\n
Interleukine-1(pg\/ml)<\/strong><\/td>\n6.450\u00a0 \u00b1\u00a0\u00a0 0.887<\/td>\n11.25 \u00b1\u00a0\u00a0\u00a0\u00a0 1.10**<\/td>\n<\/tr>\n
CRP (mg\/dl)<\/strong><\/td>\n1.940 \u00b1\u00a0\u00a0\u00a0 0.227<\/td>\n5.532 \u00b1\u00a0\u00a0\u00a0 0.566 **<\/td>\n<\/tr>\n
TNF (pg\/ml)<\/strong><\/td>\n5.8\u00a0 \u00b1\u00a0\u00a0\u00a0 14.5<\/td>\n57\u00a0 \u00b1\u00a0\u00a0\u00a0\u00a0 142*<\/td>\n<\/tr>\n
Interleukine-8 (ng\/mL)<\/strong><\/td>\n0.135\u00a0\u00a0 \u00b1\u00a0 0.339<\/td>\n1.12\u00a0\u00a0 \u00b1\u00a0\u00a0 2.80 *<\/td>\n<\/tr>\n
Interleukine-10 (pg\/ml)<\/strong><\/td>\n24.3\u00a0\u00a0 \u00b1\u00a0\u00a0 60.7<\/td>\n70\u00a0 \u00b1\u00a0\u00a0\u00a0\u00a0 176 (NS)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Correlation within Parameters<\/strong><\/p>\n

The results revealed that there was positive correlation\u00a0 between IL-6with glucose (0.178),\u00a0 CRP\u00a0 (0.131), and IL-8 (0.155), also between IL-10 with protein\u00a0 (0.265), TNF with IL-8\u00a0 (0.272),and IL-1 with CRP\u00a0 (0.106).\u00a0 whereas there was negative correlation\u00a0 between IL-6 with protein\u00a0 (-0.049), TNF (-0.221),\u00a0 IL-1 (-0.209), IL-10 (-0.036), also between IL-1 with IL-8\u00a0 (-0.176),between\u00a0 IL-10\u00a0 with(-0.110), and TNF (-0.123).between\u00a0 IL-10 with\u00a0 glucose (-0.402), CRP ( -0.065).<\/p>\n

Table 3: Correlation within Parameters<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
CHF Group \u00a0(r )<\/strong><\/td>\nparameters<\/strong><\/td>\n<\/tr>\n
\n

0.178<\/p>\n<\/td>\n

\n

IL-6 with glucose<\/p>\n<\/td>\n<\/tr>\n

\n

0.155<\/p>\n<\/td>\n

\n

IL-6 with IL-8<\/p>\n<\/td>\n<\/tr>\n

\n

-0.036<\/p>\n<\/td>\n

\n

IL-10 with IL-6<\/p>\n<\/td>\n<\/tr>\n

\n

0.131<\/p>\n<\/td>\n

\n

IL-6 with CRP<\/p>\n<\/td>\n<\/tr>\n

\n

-0.221<\/p>\n<\/td>\n

\n

TNF with IL-6<\/p>\n<\/td>\n<\/tr>\n

\n

-0.209<\/p>\n<\/td>\n

\n

IL-1 with IL-6<\/p>\n<\/td>\n<\/tr>\n

\n

-0.402<\/p>\n<\/td>\n

\n

IL-10 with\u00a0 glucose<\/p>\n<\/td>\n<\/tr>\n

\n

0.265<\/p>\n<\/td>\n

\n

IL-10 with protein<\/p>\n<\/td>\n<\/tr>\n

\n

0.106<\/p>\n<\/td>\n

\n

IL-1 with CRP<\/p>\n<\/td>\n<\/tr>\n

\n

-0.176<\/p>\n<\/td>\n

\n

IL-1 with IL-8<\/p>\n<\/td>\n<\/tr>\n

\n

-0.404<\/p>\n<\/td>\n

\n

TNF with CRP<\/p>\n<\/td>\n<\/tr>\n

\n

-0.110<\/p>\n<\/td>\n

\n

IL-1 with IL-10<\/p>\n<\/td>\n<\/tr>\n

\n

0.272<\/p>\n<\/td>\n

\n

TNF with IL-8<\/p>\n<\/td>\n<\/tr>\n

\n

-0.123<\/p>\n<\/td>\n

\n

TNF with IL-1<\/p>\n<\/td>\n<\/tr>\n

\n

-0.105<\/p>\n<\/td>\n

\n

IL-8 with\u00a0 glucose<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n


\nDiscussion<\/strong><\/p>\n

Interleukin-6 (IL-6) is a multifunctional inflammatory cytokine that plays an important role in the response to environmental stress and has been implicated in the pathogenesis of many chronic diseases.\u00a0 Interleukin-6 is a proinflammatory cytokine involved in the inflammatory response in the CNS. It is produced within CNS, i.a. by astrocytes and glial cells as a response to initiated or ongoing infection. Its production is also affected by other cytokines, i.a. TNF and IL-1. IL-6 has mainly proinflammatory properties. It persuades the synthesis of acute-phase proteins and contributes to BBB. IL-6 may act as an anti-inflammatory cytokine. It is validated by leukocyte transmission from blood to CSF(5-7)<\/sup>.The level of IL-6 is higher in patients with meningitis\u00a0 than control group. Our findings are in the line with(8,9)<\/sup>,whereas disagreement with the results obtained by Pinto et al<\/em>. (10)<\/sup>.<\/p>\n

Interleukin-10 is an acid-labile anti-inflammatory cytokine produced by monocytes, macrophages, B and T lymphocytes, brain cells such as neurons and microglia that capable of inhibiting proinflammatory responses(11,12)<\/sup>.The level of IL-10 is higher in patients with meningitis ,These findings are in harmony with preceding reports(13,14)<\/sup>.who stated that initially high IL-10 concentration gradient across the blood-brain barrier, comparably low amounts of IL-10 were detected in serum in the acute phase of meningitis, suggesting an initial compartmentalized release of IL-10 in the subarachnoid space in patients presenting with meningitis without persistent circulatory impairment.<\/p>\n

Interleukin-8 is a pro-inflammatory cytokine which \u00a0acts as a chemoattractant for neutrophils to the site of inflammation(14)<\/sup>.Serum level of IL-8 was found to be significantly elevated in patients with meningitis, Because IL-8 contributes to leucocyte extravasation during infectious meningitis of viral and bacterial origin. The role of this molecule has been implicated in the blood\u2013brain barrier disruption and meningeal infiltration by immune cells(15)<\/sup>.Similar observation was supported by (13,16)<\/sup>.<\/p>\n

Tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) a proinflammatory cytokine\u00a0 are present in the CSF which are produced in the subarachnoid space by different cells, e.g., leukocytes, astrocytes, and microglia., Therefore, TNF-a contributes to the accumulation of leukocytes in the CSF, brain edema , blood-brain barrier damage ,and damage of cells within the CNS(17)<\/sup>.TNF may leak from CSF to serum during meningitis. However, in spite of the marked leakage of protein, and the high concentration gradient of TNF across the blood-brain barrier, the negligible amounts of bioactive TNF leak from CSF to serum during meningitis. By leakage from the subarachnoid space to the systemic circulation there is a dilution factor of 10-20.<\/p>\n

Interleukin-1 (IL-1) produced within tissues and has multifunctional cytokine contributes to local inflammatory reactions, primarily complicated in the regulation of inflammatory processes, it mediates stimulation of fibroblast growth, and differentiation of B and T cells(18,20)<\/sup>.<\/p>\n

Interleukin -1 contributes to disruption of the blood-brain barrier and CSF leukocyte recruitment and stimulates the production of other cytokines, such as IL-6 and TNF-\u03b1. The recruitment of polymorphonuclear leukocytes may induce damage not only to the bacteria but also to the brain(21)<\/sup>.Our analysis revealed statistically significant increase in the level of TNF-a and IL-1 in patients compared to the control group. This result is consistent with the other studies(6,21,22)<\/sup>,whereas disagree with(23)<\/sup>.<\/p>\n

C-reactive protein is produced by the monocytes of the tissue factor which initiates the coagulation process. C-reactive protein, together with fibrinogen, acts as a chemotactic factor. Fibrinogen is responsible for the adhesion of macrophages to the endothelial surface for their migration into the intima(24)<\/sup>.Direct hepatic release of CRP in to plasma which then undergoes\u00a0 ultra-filtration to form CSF meningeal irritation stimulate CRP production. Once CRP enters the\u00a0 CSF it binds to the damaged tissues(25)<\/sup>.So that the increased CRP concentrations in patients with meningitis may stimulate production by the monocytes of the tissue factor which initiates the coagulation process(26)<\/sup>.The findings of the present study concurs with earlier studies(27,28)<\/sup>.Corral et al. found positive CSF CRP in 24\/32 patients with culture-proved bacterial meningitis, while only 2\/32 children with non-bacterial meningitis had CSF which was positive for CRP. According to Corral et al., this was a more sensitive test for differentiating bacterial from non-bacterial(29)<\/sup>.<\/p>\n

Conclusion<\/strong><\/p>\n

More studies performed in suitable models of meningitis are needed in order to establish the routine use of inflammatory markers in the diagnosis of infectious diseases of the central nervous system.<\/p>\n

Financial\u00a0and conflict interests disclosure<\/strong><\/p>\n

This work was not supported by any institution or company. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. No conflict interests of any were reported during the course of this study. We have done the work completely by our self-funding.<\/p>\n

Acknowledgments<\/strong><\/p>\n

Authors Acknowledgment is going to Kirkuk and Tikrit health\u00a0 directorate that allowed us to conduct this research in Kirkuk and Tikrit hospitals,\u00a0 in Tikrit Teaching Hospital , Kirkuk General Hospital and Kirkuk pediatric Hospital. Also, all private clinics and laboratories assisted our work . Our thanks and appreciation going to the staff, laboratory worker at Hospitals , private clinics and laboratories for their help during the enrollments of patients and sampling.<\/p>\n

References<\/strong><\/p>\n

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