Research ArticleClinical Studies

A Possible Role of Interleukin-18 Binding Protein in Immune Regulation of Postoperative Pain: A Prospective Randomized Clinical Trial

MAARET ESKELINEN, IINA SAIMANEN, JUKKA PULKKINEN, TUOMAS SELANDER, ANU HOLOPAINEN, ESA HÄMÄLÄINEN and MATTI ESKELINEN
Anticancer Research July 2023, 43 (7) 3113-3119; DOI: https://doi.org/10.21873/anticanres.16483

Abstract

Background/Aim: A possible role of interleukin-18 binding protein (IL-18BP) in immune regulation of pain and analgesics following surgery is rarely studied. The aim of this study was to investigate serum IL-18BP values in a cohort of laparoscopic cholecystectomy (LC) and minilaparotomy cholecystectomy (MC) patients and to establish their relationship with other cytokines and number of analgesic doses (NAD) of LC and MC patients postoperatively. Patients and Methods: Blood levels of IL-18BP, six other interleukins (IL-18, IL-1ra, IL-6, IL-10, IL-1β, and IL-8) and high-sensitivity C-reactive protein were measured before operation (PRE), immediately after operation (POP1), and six hours after operation (POP2) in 114 patients with cholelithiasis. Results: Following surgery, the mean serum IL-18BP values correlated significantly to numeric rating scale (NRS) pain scores at 24 hours (r=0.194, p=0.009). In addition, the mean serum IL-18BP values correlated significantly to NAD (r=0.254, p<0.001). Conclusion: IL-18BP, a soluble antagonist of IL-18, correlates to NRS and NAD in LC and MC patients, which may support a possible role of IL-18BP in immune regulation of postoperative pain.

Key Words:

Cytokines (CYTs) are regulators of the acute phase immune response (APR) to inflammation and trauma. There are two types of CYTs: pro-inflammatory CYTs enhance systematic inflammation, whereas anti-inflammatory CYTs inhibit inflammation and stimulate healing (1, 2). The major pro-inflammatory CYTs that regulate early responses include interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α). Other proinflammatory regulators include members of the IL-20 family, interferon-γ (IFNγ), oncostatin M (OSM), transforming growth factor-β (TGF-β), IL-8, IL-11, IL-12, IL-17, IL-18, IL-33, and a variety of other chemokines that affect inflammatory cells (1-7).

IL-18 binding protein (IL-18BP) is a soluble antagonist of IL-18 that binds to the IL-18 ligand. This binding of IL-18BP blocks the interaction of IL-18 with the IL-18Rα on the cell surface and eventually inhibits the IL-18 signaling pathway. Therefore, IL-18BP is considered a potent IL-18 inhibitor (5). In addition, the production of IFNγ induces IL-18BP to play a regulatory role in a negative feedback manner (5). IL-18BP is expressed in various organs, such as the spleen, small intestine, stomach, colon, placenta, and lung (5). Furthermore, IL-18 was first described as an IFNγ inducing factor (IGIF) (5) and there is evidence that IL-18 induces IFNγ under various conditions (5).

It has been hypothesized that CYT levels would influence pain scores (8-11). This assumption relies on the suggestion that inflammation could activate the opioid receptors (OpRes) and the opioid peptides (OpPep) could easily bind to the OpRes on nerve terminals, which decrease inflammatory pain (8). Chemokines and adhesion molecules moderate and enhance the migration of OpPep-containing leukocytes (Leucs) into the tissue. In addition, the endogenous OpPep produced by Leucs not only enhance analgesia, but they can also prevent the development of opioid tolerance (9).

However, the correlation of the APR and pain following surgery is rarely studied. In addition, a possible role of IL-18BP in immune regulation of postoperative pain is rarely studied. Therefore, the aim of this study was to investigate the IL-18BP levels in a cohort of laparoscopic cholecystectomy (LC) and minilaparotomy cholecystectomy (MC) patients and to establish their relationship with other CYTs and number of analgesic doses (NAD) in LC and MC patients postoperatively.

Patients and Methods

Figure 1 shows the flow-chart of the trial protocol and number of patients in the study. The study was approved by the Local Ethical Board of Eastern Finland Hospital District, Kuopio, Finland (DNRO 27/02/2013), it was registered in the ClinicalTrials.gov database (ClinicalTrials.gov Identifier: NCT01723540), and was conducted in accordance with the Declaration of Helsinki. Detailed description of the study patients and protocol was provided in previous report by Saimanen et al. (12).

Figure 1.
Figure 1.

Study flowchart.

Sample collection, processing, and interpretation of results. The blood samples were taken before surgery (PRE), immediately after surgery (POP1) and 6 h post-operatively (POP2) and centrifuged at 1,000 × g for 10 min for serum samples and 15 min for plasma samples at +20 to +25°C. The interleukin assays were performed using ELISA methods from R&D Systems (Minneapolis, MN, USA). The manufacturer’s intra-assay and the inter-assay CYTs for IL-18BP were 2.1-5.3% and 7.0-11.7%, respectively. The sensitivity of the plasma high-sensitivity C-reactive protein (hs-CRP) and other CYT assays were detailed in previous reports by Purdy et al. (13).

Statistical analysis. Baseline demographic characteristics are presented in Table I as means with standard deviations or with frequencies. The baseline group comparisons were executed by independent samples t-test and chi-square test or Fishers exact test. The blood CYT and IL-18BP concentrations in Table II and Table III are presented as median levels with interquartile range as distributions were right-skewed and differences in MC and LC groups were tested using the Mann–Whitney U-test. The differences between time points were analyzed using the Wilcoxon signed rank test. A linear mixed effect model (LME) was used to analyze group differences at time points and overall group × time effect. In the LME analysis, the CYT levels were log transformed. The Pearson’s method was used to examine the correlation of the blood IL-18BP concentration and pain score (Figure 2) and the blood IL-18BP concentration and number of analgesic doses (Figure 3). Data were analyzed by IBM SPSS statistical software (IBM SPSS Statistics for Windows, version 26.0, IBM Corporation, Armonk, NY, USA).

View this table:
Table I.

Clinical data. Data are mean (standard deviation) or number of cases.

View this table:
Table II.

The median hsCRP and cytokine levels before (PRE), immediately (POP1) and 6 h after operation (POP2) in minilaparotomy (MC) and laparoscopic cholecystectomy (LC).

View this table:
Table III.

The hsCRP and cytokine levels before (PRE), immediately (POP1) and 6 h after operation (POP2) in minilaparotomy (MC) and laparoscopic cholecystectomy (LC).

Figure 2.
Figure 2.

Scatter plots of the blood IL-18BP concentration versus pain assessed using an 11-point numeric rating scale (NRS; 0=no pain; 10=most pain) at 24 h postoperatively (NRS) (r=0.194, p=0.009).

Figure 3.
Figure 3.

Scatter plots of blood IL-18BP concentration versus number of analgesic doses (NAD) during 24 h postoperatively (r=0.254, p<0.001).

Results

The APR following surgery. The median CYT levels between study groups were quite equal. Changes in blood IL-18BP and CYT concentrations preoperatively and following surgery are shown in Table II. IL-18, IL-1ra, IL-6, and IL-10 showed a trend for increase postoperatively in study patients and the LME time-effect was statistically significant for the hs-CRP and IL-1ra biomarkers (p=0.033 and p=0.042, respectively, Table II). Table III shows the overall p-values using linear mixed-effect model; it shows the effects of different time and group interactions in all patients (two study groups together); in IL-18BP, hs-CRP, IL-1ra, IL-6, IL-10 and IL-1β biomarkers (p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, and p=0.014, respectively, Table III).

The IL-18BP versus IL-18 and NRS and NAD. The mean serum IL-18BP levels correlated significantly to mean serum IL-18 levels (r=0.254, p<0.001). However, there were no significant differences between the IL-18BP levels and hs-CRP, IL-ra, IL-6, IL-10 and IL-1β levels. There was a significant correlation between the mean serum IL-18BP values and NRS pain scores during the first 24 h following surgery (r=0.194, p<0.009, Figure 2). In addition, the mean serum IL-18BP values correlated significantly to the number of analgesic doses (NAD) during 24 h postoperatively (r=0.254, p<0.001).

Discussion

Controlling severe postoperative pain is perceived a very prominent factor for improving the satisfaction of patients postoperatively. Since the grade of pain and the effect of analgesics differs among patients, biomarkers of opioid treatment have been assessed to enhance the potency of analgesics (1, 11, 14-16). Pilat et al. showed (14), that blockade of IL-18 signaling reduced neuropathic pain and improved the potency of analgesics. Authors concluded (14), that CYT signaling is closely linked with pain and there is synergy between CYTs and OpRes (14). However, only few studies have assessed the blood levels of CYTs versus NRS and analgesics following surgery.

Makimura et al. (1) investigated the plasma CYTs in order to detect potential markers to anticipate resistance to morphine treatment in a cohort of opioid-treatment-naïve cancer patients. They reported NRS scores and the plasma levels of CYTs at baseline and after morphine treatment using a immunoassay for the following CYTs: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GMCSF), interferon α2 (IFN-α2), IFN-γ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, TNFα and TNF-β. However, Makimura et al. (1) found no correlation between the cancer patients clinical data and NRS pain scores at baseline or among patients who generated resistance to morphine treatment. Interestingly, the plasma level of MIP-1α significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma CYT levels, none of the CYTs were correlated with the NRS scores at baseline; however, the baseline plasma levels of MIP-1α and MIP-1β were significantly lower in patients who needed a high dose of morphine or who generated resistance to morphine treatment. MIP-1α was earlier identified as a macrophage inflammatory protein that has inflammatory and neutrophil chemokinetic properties (17). MIP-1α plays various roles in inflammatory responses by binding to chemokine receptors (17). Interestingly, Makimura et al. (1) concluded that plasma MIP-1α could be a novel biomarker for following the effects of morphine treatment.

Heitzer et al. (11) analyzed biomarkers in 38 patients and found that five CYTs, IL-7, IL-18, MCP-1, MIP-1α, MIP-1β and osteoprotegerin (OPG), correlated significantly with pain relief in NRS scores. They concluded that IL-7, IL-18, MCP-1, MIP1-β and OPG may serve as biomarkers for pain perception and/or pain reduction and a tool for objective diagnostic score for estimation of pain. In addition, they considered that these CYTs could serve as potential targets for development of new analgesics. Heitzer et al. (11) provided evidence of a significant correlation between CYTs and pain in cancer patients. From a clinical view, it would be of great interest to have markers to estimate pain intensity/easement in an objective manner based on biochemical findings (14). The study of Muallem et al. (18) presented means to generate a certain protocol for postoperative pain therapy (ERAS, enhanced recovery after surgery protocol), which was recommended to use in surgical patients, because this protocol guarantees efficient pain management allowing rapid mobilization of the patient (18). In addition, specific CYT antagonists could provide non-opioid analgesics of severe pain (9, 10, 14, 15, 16).

The main result in this work is that IL-18BP, a soluble antagonist of IL-18, correlates to NRS and NAD in LC and MC patients. The pattern of IL-18BP levels versus NRS and NAD values support the suggestion that the APR and pain are correlated. The underlying mechanism explaining why this CYT antagonist correlates with pain and analgesics remains unclear. A possible hypothesis could be OpRes-signaling. The activation of OpRes may block the function of chemokine receptors on Leucs via a calcium-independent protein kinase C pathway (19). In addition, Leuc subpopulations in the peripheral blood such as lymphocytes, monocytes, and granulocytes, produce OpPep, such as met-enkephalin, β-endorphin, dynorphin, and endomorphins, in inflammatory peripheral tissue (20). OpPep can bind to OpRes on sensory neurons and decrease analgesia in inflammatory tissue (21-23). Since chemokines control the migration of OpPep-expressing Leucs (21-23), the antinociceptive effects of chemokines may be involved in the outcome of analgesics.

Interestingly, Marino et al. (24) assessed the role of APR in the outcome of SARS-CoV-2 infection patients. Since, IL-18 is signalling the host response to viral infection, they measured the serum levels of IL-18, IL-18BP, INF-γ at the onset of the SARS-CoV-2 infection. They divided the patients in two severity groups according to the arterial pressure of oxygen and fraction of inspired oxygen and by computerized tomography at the admittance. In the group of patients with a more severe disease, a significant increase in IL-18, INF-γ, and IL-18BP levels were observed, whereas the serum IL-18 values were almost constant. Furthermore, Marino et al. (24) concluded that IL-18BP is a promising prediction biomarker and possible therapeutic target for SARS-CoV-2 infection patients.

Nasser et al. (25) measured IL-18 and IL-18BP levels in SARS-CoV-2 infection patients and correlated the biomarker levels to severity and mortality of SARS-CoV-2 disease. Their results showed that elevated free IL-18 levels in SARS-CoV-2 infection patients are associated with poor outcome and higher mortality. Nasser et al. (25) concluded that the results support the suggestion that life-threatening COVID-19 may be a Macrophage Activation Syndrome-like disease and may benefit from IL-18 modulation therapy.

A core result of this study is that IL-18BP, a soluble antagonist of IL-18, correlates to NRS and NAD in LC and MC patients. In addition, the correlation of IL-18BP levels versus NRS and NAD values support a role of IL-18BP in immune regulation of postoperative pain.

Acknowledgements

The study was funded by the North Savo Regional Fund (Pohjois-Savon Maakuntarahasto).

Footnotes

  • Authors’ Contributions

    Maaret Eskelinen, Iina Saimanen and Matti Eskelinen contributed to the collection and analysis of data, drafting, and revising the manuscript, read and approved the final article. Jukka Pulkkinen, Tuomas Selander, Anu Holopainen, and Esa Hämäläinen contributed to the analysis of data, drafting, and revising the manuscript, read and approved the final article.

  • Conflicts of Interest

    The Authors report no conflicts of interest or financial ties in relation to this study.

  • Received March 21, 2023.
  • Revision received May 2, 2023.
  • Accepted May 3, 2023.

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A Possible Role of Interleukin-18 Binding Protein in Immune Regulation of Postoperative Pain: A Prospective Randomized Clinical Trial
MAARET ESKELINEN, IINA SAIMANEN, JUKKA PULKKINEN, TUOMAS SELANDER, ANU HOLOPAINEN, ESA HÄMÄLÄINEN, MATTI ESKELINEN
Anticancer Research Jul 2023, 43 (7) 3113-3119; DOI: 10.21873/anticanres.16483
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